Dihydropyrrolonaphthyridinone compounds as inhibitors of jak

ABSTRACT

Disclosed are JAK inhibitors of formula I 
     
       
         
         
             
             
         
       
     
     where G 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 12/796,583, filed Jun.8, 2010, which claims the benefit of U.S. Provisional Application No.61/185,157, filed Jun. 8, 2009, which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to medicinal chemistry and pharmaceuticalscience. Provided herein are compounds that inhibit Janus kinase (JAK).

BACKGROUND OF THE INVENTION

The Janus Kinases (JAK) are a family of cytoplasmic protein tyrosinekinases including JAK1, JAK2, JAK3 and TYK2. Each of the JAK kinases isselective for the receptors of certain cytokines, though multiple JAKkinases may be affected by particular cytokine or signaling pathways,including the pathways for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

Phosphorylated JAK kinases bind various Signal Transducer and Activatorof Transcription (STAT) proteins. STAT proteins are DNA binding proteinsactivated by phosphorylation of tyrosine residues and function both assignaling molecules and transcription factors and bind to specific DNAsequences of promoters of cytokine-responsive genes.

Cytokines influence cell differentiation, proliferation, and activation.Cytokines modulate both inflammatory and immune responses.

Abnormal JAK/STAT signaling is observed in conditions, such asallergies, asthma, autoimmune diseases such as transplant rejection,rheumatoid arthritis, amyotrophic lateral sclerosis, and multiplesclerosis, as well as in solid and hematologic malignancies such asleukemia and lymphomas. Inhibitors of the JAK pathway, particularlyJAK3, are thought to be therapeutically useful for treating suchconditions.

Certain JAK inhibitors are disclosed in WO 2007/077949 and WO2008/084861.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I,

or pharmaceutically acceptable salts thereof, wherein:

-   G₁ is selected from the group consisting of N and CR₈;-   R₁ is selected from the group consisting of optionally substituted    C₃₋₈ cycloalkyl, optionally substituted C₃₋₆ heterocycloalkyl,    optionally substituted C₄₋₁₄ aryl, optionally substituted C₁₋₁₀    heteroaryl, and optionally substituted C₁₋₆ alkyl;-   R₂ and R₃ are each independently selected from the group consisting    of hydrogen and optionally substituted C₁₋₄ alkyl, or R₂, R₃, and    the carbon atom to which they are attached form a carbonyl;-   R₄ is selected from the group consisting of hydrogen, optionally    substituted C₁₋₄ alkyl, optionally substituted C₁₋₄ alkoxy, halo,    hydroxy, and amino;-   R₅ is selected from the group consisting of hydrogen, optionally    substituted C₁₋₄ alkyl, C₃₋₈ cycloalkyl, and halo;-   R₆ and R₇ are each independently selected from the group consisting    of hydrogen and optionally substituted C₁₋₄ alkyl, or R₆, R₇, and    the carbon atom to which they are attached form a carbonyl;-   R₈ is selected from the group consisting of hydrogen, optionally    substituted C₁₋₆ alkyl, optionally substituted C₁₋₄ alkoxy, C₁₋₉    amide, C₁₋₅ oxycarbonyl, cyano, optionally substituted C₃₋₈    cycloalkyl, optionally substituted C₄₋₁₄ aryl, optionally    substituted C₁₋₁₀ heteroaryl, and halo; and    with the proviso that no more than one carbonyl is formed from R₂    and R₃ and R₆ and R₇.

One aspect of the invention provides a pharmaceutical composition, whichincludes a compound of formula I or a pharmaceutically acceptable saltas defined above, and a pharmaceutically acceptable excipient.

Another aspect of the invention provides a use as a medicament of acompound of formula I or a pharmaceutically acceptable salt as definedabove.

An additional aspect of the invention provides a use of a compound offormula I or a pharmaceutically acceptable salt as defined above, forthe manufacture of a medicament for the treatment of a disease, disorderor condition associated with JAK.

A further aspect of the invention provides a method of treating adisease, disorder or condition associated with JAK in a subject, themethod comprising administering to the subject an effective amount of acompound of formula I or a pharmaceutically acceptable salt as definedabove.

An additional aspect of the invention provides a method of treating adisease or condition in a subject, the method comprising administeringto the subject an effective amount of a compound of formula I or apharmaceutically acceptable salt as defined above, wherein the diseaseor condition is selected from allergic rhinitis, allergic asthma, atopicdermatitis, rheumatoid arthritis, multiple sclerosis, systemic lupuserythematosus, psoriasis, immune thrombocytopenic purpura, chronicobstructive pulmonary disease, and thrombosis.

Another aspect of the invention provides a method of treating a diseaseor condition in a subject, the method comprising administering to thesubject an effective amount of a compound of formula I or apharmaceutically acceptable salt as defined above, wherein the diseaseor condition is selected from a hematological malignancy and anepithelial cancer.

A further aspect of the invention provides a combination of an effectiveamount of a compound of formula I or a pharmaceutically acceptable saltas defined above, and at least one additional pharmacologically activeagent.

The present invention also provides an article of manufacture comprisingat least one compound of formula I and a label. Also provided are kits,which comprises at least one compound of formula I, a label, andapparatus for administration of the inhibitor.

The present invention also provides processes from making JAK inhibitorsand intermediates thereof.

Compounds of this invention include all pharmaceutically acceptablecomplexes, salts, solvates, and hydrates of the compounds. Compounds ofthis invention also include all stereoisomers, tautomers, andpolymorphic forms of the compounds, including all crystalline andamorphous forms, whether they are pure, substantially pure, or mixtures.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated, this disclosure uses definitions providedbelow.

The term “substituted,” when used in connection with a chemicalsubstituent or moiety (e.g., an alkyl group), means that one or morehydrogen atoms of the substituent or moiety have been replaced with oneor more non-hydrogen atoms or groups, provided that valence requirementsare met and that a chemically stable compound results from thesubstitution.

The terms “about” or “approximately,” when used in connection with ameasurable numerical variable, refers to the indicated value of thevariable and to all values of the variable that are within theexperimental error of the indicated value (e.g., within the 95%confidence interval for the mean) or within ±10 percent of the indicatedvalue, whichever is greater.

The term “C₂₋₄ alkenyl” refers to a straight or branched alkenyl chainhaving from two to four carbon atoms and one or more carbon-carbondouble bonds, and includes ethylene, propylene, isopropylene, butylene,isobutylene, sec-butylene, and the like.

The term “C₁₋₄ alkyl” refers to a straight or branched alkyl chainhaving from one to four carbon atoms.

The term “optionally substituted C₁₋₄ alkyl” refers to a C₁₋₄ alkyloptionally having from 1 to 5 substituents independently selected fromthe group consisting of amino, C₁₋₇ amido, C₁₋₈ alkylamino, C₂₋₄alkenyl, C₁₋₄ alkoxy, C₁₋₄ thioalkoxy, C₁₋₉ amide, C₁₋₅ oxycarbonyl,cyano, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, halo, hydroxy, oxo, C₁₋₈sulfonyl, optionally substituted C₁₋₁₀ heteroaryl, optionallysubstituted C₃₋₆ heterocycloalkyl, optionally substituted C₁₋₁₀heteroaryl, and optionally substituted phenyl.

The term “C₁₋₆ alkyl” refers to a straight or branched alkyl chainhaving from one to six carbon atoms.

The term “optionally substituted C₁₋₆ alkyl” refers to a C₁₋₆ alkyloptionally having from 1 to 7 substituents independently selected fromthe group consisting of amino, C₁₋₇ amido, C₁₋₈ alkylamino, C₂₋₄alkenyl, C₁₋₄ alkoxy, C₁₋₄ thioalkoxy, C₁₋₁₄ amide, C₁₋₅ oxycarbonyl,cyano, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, halo, hydroxy, oxo, C₁₋₈sulfonyl, optionally substituted C₁₋₁₀ heteroaryl, optionallysubstituted C₃₋₆ heterocycloalkyl, optionally substituted C₁₋₁₀heteroaryl, and optionally substituted phenyl.

The term “C₁₋₈ sulfonyl” refers to a sulfonyl linked to a C₁₋₆ alkylgroup, C₃₋₈ cycloalkyl, or an optionally substituted phenyl.

The term “C₁₋₄ alkoxy” refers to a C₁₋₄ alkyl attached through an oxygenatom.

The term “optionally substituted C₁₋₄ alkoxy” refers to a C₁₋₄ alkoxyoptionally having from 1 to 6 substituents independently selected fromthe group consisting of C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₅oxycarbonyl, cyano, C₃₋₈ cycloalkyl, halo, hydroxy, optionallysubstituted C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

The term “C₁₋₉ amide” refers to an amide having two groups independentlyselected from the group consisting of hydrogen and C₁₋₄ alkyl, e.g.,—CONH₂, —CONHCH₃, and —CON(CH₃)₂.

The term “C₁₋₁₄ amide” refers to an amide (a) having two groups attachedto the nitrogen atom which are independently selected from hydrogen andoptionally substituted C₁₋₄ alkyl, e.g., —CONH₂, —CONHCH₃, and—CON(CH₃)₂; or an amide (b) having a hydrogen and a non-hydrogensubstituent on nitrogen, wherein the non-hydrogen substituent isselected from optionally substituted C₁₋₄ alkyl, optionally substitutedC₁₋₄ alkoxy, optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₃₋₆ heterocycloalkyl, optionally substituted C₄₋₁₄ aryl,and optionally substituted C₁₋₁₀ heteroaryl, e.g., —CONH-(cyclopentyl),—CONH-(aryl), —CONH—CH₂-(phenyl), and so on.

The term “C₁₋₇ amido” refers to a —NHC(O)R group in which R is C₁₋₆alkyl.

The term “C₁₋₅ carbamoyl” refers to an O- or N-linked carbamate having aterminal C₁₋₄ alkyl.

The term “C₁₋₅ ureido” refers to a urea having a C₁₋₄ alkyl.

The term “C₁₋₈ alkylamino” refers to an amino having one or two C₁₋₄alkyl.

The term “C₄₋₁₄ aryl” refers to a monocyclic or polycyclic unsaturated,conjugated hydrocarbon having aromatic character and having four tofourteen carbon atoms, and includes phenyl, biphenyl, indenyl,cyclopentyldienyl, fluorenyl, and naphthyl.

The term “optionally substituted C₄₋₁₄ aryl” refers to a C₄₋₁₄ aryloptionally having 1 to 5 substituents independently selected from thegroup consisting of amino, C₁₋₈ alkylamino, C₁₋₇ amido, C₁₋₅ carbamoyl,C₁₋₆ sulfonylamido, C₀₋₆ sulfonylamino, C₁₋₅ ureido, optionallysubstituted C₁₋₄ alkyl, optionally substituted C₁₋₄ alkoxy, cyano,halogen, hydroxy, nitro, C₁₋₅ oxycarbonyl, and C₁₋₈ sulfonyl.

The term “C₁₋₅ oxycarbonyl” refers to an oxycarbonyl group (—CO₂H) andC₁₋₄ alkyl ester thereof.

The term “C₃₋₈ cycloalkyl” refers to an alkyl ring having from three toeight carbon atoms, and includes cyclopropyl, 2-methyl cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “optionally substituted C₃₋₈ cycloalkyl” refers to a C₃₋₈cycloalkyl optionally having from 1 to 6 substituents independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₇ amido, C₁₋₈ alkylamino, C₁₋₅oxycarbonyl, cyano, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, halo, hydroxy,nitro, oxo, optionally substituted C₁₋₁₀ heteroaryl, and optionallysubstituted phenyl.

The term “C₃₋₈ cycloalkoxy” refers to a C₃₋₈ cycloalkyl attached throughan oxygen atom.

The terms “halogen” and “halo” refer to chloro, fluoro, bromo or iodo.

The term “C₃₋₆ heterocycloalkyl” refers to a 4 to 10 membered monocyclicsaturated or partially (but not fully) unsaturated ring having one tofour heteroatoms selected from the group consisting of nitrogen, oxygen,and sulfur. The nitrogen and sulfur heteroatoms may optionally beoxidized. For example, the term includes azetidine, pyrrolidine,piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran,hexahydropyrimidine, tetrahydropyrimidine, dihydroimidazole, and thelike.

The term “optionally substituted C₃₋₆ heterocycloalkyl” refers to a C₃₋₆heterocycloalkyl optionally substituted on the ring carbons with 1 to 4substituents independently selected from the group consisting ofoptionally substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₉amide, C₁₋₇ amido, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈cycloalkyl, C₃₋₈ cycloalkoxy, halo, hydroxy, nitro, oxo, and optionallysubstituted phenyl; and optionally substituted on any ring nitrogen witha substituent selected from the group consisting of optionallysubstituted C₁₋₄ alkyl, C₂₋₄ alkenyl, C₃₋₈ cycloalkyl, optionallysubstituted C₃₋₆ heterocycloalkyl, optionally substituted C₁₋₁₀heteroaryl, optionally substituted phenyl, and C₁₋₈ sulfonyl.

The term “C₁₋₁₀ heteroaryl” refers to a five to twelve memberedmonocyclic and polycyclic having unsaturated, conjugated ring(s) havingaromatic character and having one to ten carbon atoms and one or more,typically one to four, heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. For example, the term includes azepine,diazepine, furan, thiophene, imidazole, isothiazole, isoxazole,oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, thiazole, thiadiazole, triazole, tetrazole, benzazepine,benzodiazepine, benzofuran, benzothiophene, benzimidazole,imidazopyridine, pyrazolopyridine, pyrrolopyridine, quinazoline,thienopyridine, indolizine, imidazopyridine, quinoline, isoquinoline,indole, isoindole, benzoxazole, benzoxadiazole, benzopyrazole,benzothiazole, and the like.

The term “optionally substituted C₁₋₁₀ heteroaryl” refers to a C₁₋₁₀heteroaryl optionally having 1 to 5 substituents on carbon independentlyselected from the group consisting of amino, C₁₋₇ amido, C₁₋₈alkylamino, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido, C₀₋₆ sulfonylamino, C₁₋₅ureido, optionally substituted C₁₋₄ alkyl, optionally substituted C₁₋₄alkoxy, cyano, halogen, hydroxy, oxo, nitro, C₁₋₅ oxycarbonyl, and C₁₋₈sulfonyl, and optionally having substituents on each nitrogenindependently selected from the group consisting of optionallysubstituted C₁₋₄ alkyl, C₁₋₈ sulfonyl, optionally substituted C₃₋₆heterocycloalkyl, and optionally substituted phenyl.

The term “oxo” refers to an oxygen atom having a double bond to thecarbon to which it is attached to form the carbonyl of a ketone,aldehyde, or amide. It is understood that the oxo can be attached to anyavailable position on the group which has the oxo substituent. Forexample, an acetyl radical (—C(O)CH₃) is contemplated as an oxosubstituted alkyl group and a pryidone radical is contemplated as oxosubstituted C₁₋₁₀ heteroaryl.

The term “optionally substituted phenyl” refers to a phenyl groupoptionally having 1 to 5 substituents independently selected from thegroup consisting of amino, C₂₋₄ alkenyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉amide, C₁₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, halogen, hydrogen,hydroxy, nitro, C₁₋₈ sulfonyl, and trifluoromethyl.

The term “C₁₋₆ sulfonylamido” refers to a —NHS(O)₂—R group wherein R isC₁₋₆ alkyl.

The term “C₀₋₆ sulfonylamino” refers to a —S(O)₂NH—R group wherein R isselected from the group consisting of hydrogen and C₁₋₆ alkyl.

The term “C₁₋₄ thioalkoxy” refers to a C₁₋₄ alkyl attached through asulfur atom.

The term “opposite enantiomer” refers to a molecule that is anon-superimposable mirror image of a reference molecule, which may beobtained by inverting all of the stereogenic centers of the referencemolecule. For example, if the reference molecule has S absolutestereochemical configuration, then the opposite enantiomer has Rabsolute stereochemical configuration. Likewise, if the referencemolecule has S,S absolute stereochemical configuration, then theopposite enantiomer has R,R stereochemical configuration, and so on.

The term “stereoisomers,” when used in connection with a compound withgiven stereochemical configuration refers to the opposite enantiomer ofthe compound and to any diastereoisomers, including geometrical isomers(Z/E) of the compound. For example, if a compound has S,R,Zstereochemical configuration, its stereoisomers would include itsopposite enantiomer having R,S,Z configuration, and its diastereomershaving S,S,Z configuration, R,R,Z configuration, S,R,E configuration,R,S,E configuration, S,S,E configuration, and R,R,E configuration. Ifthe stereochemical configuration of a compound is not specified, then“stereoisomers” refers to possible stereochemical configurations of thecompound.

The phrase “substantially pure stereoisomer” and variants thereof referto a sample containing a stereoisomer which comprises at least about 95%of the sample.

The phrase “pure stereoisomer” and variants thereof refer to a samplecontaining a stereoisomer which comprises at least about 99.5% of thesample.

The phrase “pharmaceutically acceptable” refers to those substanceswhich are within the scope of sound medical judgment suitable for use incontact with the tissues of patients without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit-to-risk ratio, and effective for their intended use.

The term “excipient” refers to any substance that may influence thebioavailability of a drug, but is otherwise pharmacologically inactive.

The term “pharmaceutically acceptable salt” refers to salts ofpharmaceutically acceptable organic acids and bases or inorganic acidsand bases. Potentially useful acid addition and base salts are describedin S. M. Berge et al., J. Pharm. Sci. (1977) 66:1-19 and in Stahl andWermuth, Handbook of Pharmaceutical Salts: Properties, Selection, andUse (2002). Examples of pharmaceutically acceptable salts include thehydrochloride and mesylate salts.

It is understood that, where the terms defined herein mention a numberof carbon atoms, that the mentioned number refers to the mentioned groupand does not include any carbons that may be present in any optionalsubstituent(s).

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as isomers. All mixtures of stereoisomers, inany ratio, and specific geometric isomers, enantiomers, anddiastereomers of the compounds of the invention are contemplated to bewithin the scope of the present invention.

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as tautomers. All tautomeric forms the compoundsof the invention are contemplated to be within the scope of the presentinvention.

The phrase “compounds of the invention” refers to the compounds definedby formula I and specific compounds which fall within the scope offormula I, including compounds specifically named in the specification,examples, and claims.

Table 1 lists abbreviations used throughout the specification.

TABLE 1 List of Abbreviations Abbreviation Description Ac acetyl AcCNacetonitrile AcOH acetic acid AIBN azo-bis-isobutyronitrile APCIatmospheric pressure chemical ionization API active pharmaceuticalingredient aq aqueous Boc t-butoxycarbonyl BOPbenzotriazol-1-yloxy-tris-(dimethylamino)- phosphoniumhexafluorophosphate BSA bovine serum albumin n-Bu normal butyl Cbzcarbobenzyloxy CYP cytochrome P450 DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCC 1,3-dicyclohexylcarbodiimide DCEdichloroethane DCM dichloromethane de diastereomeric excess deenantiomeric excess DIPEA N,N-diisopropylethylamine (Hünig's Base) DMAN,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMARD diseasemodifying antirheumatic drug DMF N,N-dimethylformamide DMSOdimethylsulfoxide DMT-MM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride dppf 1,1′-bis(diphenylphosphino)ferroceneDTT dithiothreitol EDA (Brj ®35) ethoxylated dodecyl alcohol EDCN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide EDTAethylenediaminetetraacetic acid eq equivalents er enantiomeric ratio ESIelectrospray ionization Et ethyl Et₃N triethyl-amine EtOAc ethyl acetateEtOH ethyl alcohol FAM 5-carboxyfluorescein FDPP pentafluorophenyldiphenylphosphinate GC gas chromatography h, min, s hour(s), minute(s),second(s) HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) HBTU2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate(V) HEPES4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid HMPAhexamethylphosphoramide HOAt 1-hydroxy-7-azabenzotriazole HOBt1H-benzo[d][1,2,3]triazol-1-ol HODhbt3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine HPLC high performanceliquid chromatography IC₅₀ concentration at 50% inhibition IPEisopropylether i-Pr isopropyl i-PrOH isopropyl alcohol LAH lithiumaluminum hydride LC-MS liquid chromatography-mass spectrometry LDAlithium diisopropylamide Me methyl MEK methylethylketone or butan-2-oneMeOH methyl alcohol MOI multiplicity of infection mp melting point MTBEmethyl tertiary butyl ether NaOt-Bu sodium tertiary butoxide NBSN-bromosuccinimide NIS N-iodosuccinimide NMM N-methylmorpholine NMPN-methylpyrrolidone NMR, s, d, t, q, m, br nuclear magnetic resonance,singlet, doublet, triplet, quartet, multiplet, broad PE petroleum etherPh phenyl pIC₅₀, −log₁₀(IC₅₀), where IC₅₀ is given in molar (M) units Prpropyl psi pounds per square inch PyBOP (1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1- ylphosphoniumhexafluorophosphate(V) R_(f) response factor rt room temperature(approximately 20° C. to 25° C.) SEM (2-(trimethylsilyl)ethoxy)methylTATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate TCEP tris(2-carboxyethyl)phosphineTFA trifluoroacetic acid THF tetrahydrofuran TLC thin-layerchromatography Tris buffer 2-amino-2-hydroxymethyl-propane-1,3-diolbuffer Ts tosyl w/w or wt % weight (mass) percent

This disclosure concerns compounds of formula I, including compoundsspecifically named in the specification and claims, and theirpharmaceutically acceptable complexes, salts, solvates and hydrates.This disclosure also concerns materials and methods for preparingcompounds of formula I, pharmaceutical compositions containing them, andtheir use for treating disorders, diseases, and conditions involving theimmune system and inflammation, including rheumatoid arthritis, as wellas hematological malignancies, epithelial cancers (i.e., carcinomas),and other diseases, disorders or conditions associated with JAK.Compounds of formula I include the following embodiments.

a. One embodiment relates to compounds formula I in which R₄ is selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, and halo.

b. Another embodiment relates to compounds of formula I in which R₅ isselected from the group consisting of hydrogen and C₁₋₄ alkyl.

c. Another embodiment relates to compounds of formula I in which R₄ ishydrogen.

d. Another embodiment relates to compounds of formula I in which R₅ ishydrogen.

e. Another embodiment relates to compounds of formula I in which each ofR₄ and R₅ is hydrogen.

f. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, and e, in which G informula I is CR₈.

g. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, and e, in which G informula I is CR₈, and R₈ is selected from the group consisting ofhydrogen, halo, and optionally substituted C₁₋₆ alkyl.

h. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, and e, in which G informula I is CR₈, and R₈ is selected from the group consisting ofhydrogen, halo, and C₁₋₄ alkyl.

i. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, and e, in which G informula I is CR₈, and R₈ is halo.

j. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, and e, in which G informula I is CR₈, and R₈ is C₁₋₄ alkyl.

k. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, and e, in which G informula I is CR₈, and R₈ is methyl.

l. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, and e, in which G informula I is N.

m. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is optionally substituted C₃₋₈ cycloalkyl.

n. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is optionally substituted C₃₋₆heterocycloalkyl.

o. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is a nitrogen containing C₃₋₆ heterocycloalkylsubstituted on a ring carbon with C₁₋₄ alkyl and substituted on a ringnitrogen with optionally substituted C₁₋₄ alkyl.

p. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is optionally substituted C₄₋₁₄ aryl.

q. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is optionally substituted C₁₋₁₀ heteroaryl.

r. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is optionally substituted C₁₋₆ alkyl.

s. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is C₁₋₆ alkyl having an oxo substituent and anoptionally substituted C₃₋₆ heterocycloalkyl.

t. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is C₁₋₆ alkyl having an oxo substituent and anoptionally substituted C₃₋₆ heterocycloalkyl attached to the same carbonatom of the C₁₋₆ alkyl group.

u. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, and l,in which R₁ in formula I is C₁₋₆ alkyl substituted with C₁₋₁₄ amide.

v. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, l, m,n, o, p, q, r, s, t, and u, in which R₂ and R₃ in formula I, togetherwith the carbon atom to which they are attached, form a carbonyl.

w. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, l, m,n, o, p, q, r, s, t, and u, in which R₂ and R₃ in formula I, togetherwith the carbon atom to which they are attached, form a carbonyl, andeach of R₆ and R₇ in formula I is hydrogen.

x. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, l, m,n, o, p, q, r, s, t, and u, in which R₆ and R₇ in formula I, togetherwith the carbon atom to which they are attached, form a carbonyl.

y. Another embodiment relates to compounds of formula I, and optionallyany one of the above embodiments a, b, c, d, e, f, g, h, i, j, k, l, m,n, o, p, q, r, s, t, and u, in which R₆ and R₇ in formula I, togetherwith the carbon atom to which they are attached, form a carbonyl, andeach of R₂ and R₃ in formula I is hydrogen.

The compounds of the invention can be prepared by a variety ofprocedures, some of which are described below. All substituents, unlessotherwise indicated, are as previously defined. The products of eachstep can be recovered by conventional methods including extraction,evaporation, precipitation, chromatography, filtration, trituration,crystallization, and the like. The procedures may require protection ofcertain groups, for example hydroxy, amino, or carboxy groups, to avoidunwanted reactions. The selection, use, and removal of protecting groupsis well known and appreciated as standard practice, for examples see T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry,John Wiley and Sons (1991).

Scheme A depicts the formation of a compound of formula I in which R₂and R₃ are taken together with the carbon atom to which they areattached to form a carbonyl (formula IA).

Scheme A, step 1, depicts the reaction of an appropriate compound offormula (a) with an appropriate compound of formula (b) to give acompound of formula (c). An appropriate compound of formula (a) is onein which G₁, R₄, and R₆/R₇ are as desired in the final compound offormula IA or gives rise to G₁, R₄, and R₆/R₇ as desired in the finalcompound of formula IA and G₂ is hydrogen or a protecting group and G₃is C₁₋₄ alkyl, particularly methyl or ethyl. Compounds of formula (a)are readily prepared by a variety of methods including formylation ofalkyl-pyrrolopyridine-4-carboxylate oralkyl-pyrrolopyrimidine-4-carboxylate and if desired by subsequentelaboration involving additions of organometallic reagents, oxidations,conversion to halogen and other reactions well known in the art. Anappropriate compound of formula (b) is one in which R₁ is as desired inthe final compound of formula IA or gives rise to R₁ as desired in thefinal compound of formula IA.

Specifically, Scheme A, step 1, depicts the reductive amination of acompound of formula (a) with an appropriate compound of formula (b) togive a compound of formula (c). For example, reductive aminations arecarried out under a variety of conditions using reducing agents, such assodium borohydride, sodium triacetoxyborohydride, zinc/hydrochloricacid, zinc borohydride, sodium cyanoborohydride, and the like. Thereaction is carried out in a solvent, such as methanol, THF, and thelike. Typically the reaction is carried out at a temperature which mayrange from about 0° C. to about 60° C. and typically requires from about1 to about 24 hours to complete. When using sodium cyanoborohydride thereaction is carried out in a solvent, such as methanol, ethanol,isopropanol, and water or mixtures thereof. As is well known in the art,it may be advantageous to monitor and adjust the pH during suchreactions.

Alternatively, such reductive amination reactions can be carried out byhydrogenation over a catalyst. A variety of catalysts are suitable forthis purpose, including palladium, platinum, and nickel catalysts. Suchhydrogenations are carried out in a suitable solvent such as ethylacetate, ethanol, methanol, isopropanol, and the like, and are carriedout at a pressure which may range from about atmospheric to about 300psi (2068 kPa) and at a temperature which may range from about roomtemperature to about 100° C.

Scheme A, step 2, depicts the conversion of a compound of formula (c) togive a compound of formula (d). It will be recognized that theconversion of an ester to an acid is a common transformation and thatthere are numerous methods for effecting such a reaction, includinghydrolysis using various acids and bases in water containing solvents.

Scheme A, step 3, depicts the formation of an amide bond converting acompound of formula (d) to a compound of formula IA. Such amide formingreactions are well understood and appreciated in the art. For example,standard amide forming conditions can be used, such as those usingcoupling agents, including those used in peptide couplings, such as2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (HATU), 1,3-dicyclohexylcarbodiimide (DCC), andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride. Ifnecessary or desired, an additive such as 4-(dimethylamino)pyridine,1H-benzo[d][1,2,3]triazol-1-ol (HOBt), and the like may be used tofacilitate the reaction. Such reactions are generally carried out usinga base, such as N-methylmorpholine or triethylamine, in a wide varietyof suitable solvents such as dichloromethane, dimethylformamide, THF,and the like.

Scheme B depicts the formation of a compound of formula I in which R₆and R₇ are taken together with the carbon atom to which they areattached to form a carbonyl (formula IB). The process steps in Scheme Bare the same as those depicted in Scheme A. However, the startingmaterial, a compound of formula (a′), has a —C(O)OG₃ group in the3-position and a carbonyl group (—C(O)—R₂/R₃) in the 4-position, whichresults in an oxo substitution at R₆ and R₇ of formula IA.

The processes depicted in Schemes A and B may be varied as desired. Forexample, protecting groups may be added or removed at various stepsalong the routes depicted in Schemes A and B. Also, a compound formed instep 3 can be further elaborated to give R₁ as desired in the finalproduct, via alkylations, acylations, hydrolysis, oxidation, reduction,amidations, sulfonations, alkynations, alkyenations, and the like.

Also, in an optional step, not shown, a compound of formula I can beconverted to a pharmaceutically acceptable salt. For example, a compoundof formula I may be reacted with an appropriate acid or base to give thedesired salt. Alternatively, a precursor of the compound of formula Imay be reacted with an acid or base to remove an acid- or base-labileprotecting group or to open a lactone or lactam group of the precursor.Additionally, a salt of the compound of formula I may be converted toanother salt through treatment with an appropriate acid or base orthrough contact with an ion exchange resin. Following reaction, the saltmay be isolated by filtration if it precipitates from solution or may berecovered by evaporation. The degree of ionization of the salt may varyfrom completely ionized to almost non-ionized.

Useful salts of the compound of formula I may include acid additionsalts (including di-acids) and base addition salts. Pharmaceuticallyacceptable acid addition salts may include nontoxic salts derived frominorganic acids such as hydrochloric acid, nitric acid, phosphoric acid,sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, andphosphorous acids, as well nontoxic salts derived from organic acids,such as aliphatic mono- and dicarboxylic acids, phenyl-substitutedalkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromaticacids, aliphatic and aromatic sulfonic acids, etc. Such salts includeacetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate,bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate,hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate,stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate andxinofoate salts.

Useful base addition salts may include nontoxic salts derived frombases, including metal cations, such as an alkali or alkaline earthmetal cation, as well as amines. Examples of suitable metal cations mayinclude sodium (Na⁺), potassium (K⁺), magnesium (Mg²⁺), calcium (Ca²⁺),zinc (Zn²⁺), and aluminum (Al³⁺). Examples of suitable amines mayinclude arginine, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine,glycine, lysine, N-methylglucamine, olamine,2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine.

The compounds of the invention can be administered alone or in the formof a pharmaceutical composition. In practice, the compounds of theinvention are usually administered in the form of pharmaceuticalcompositions, that is, in admixture with at least one pharmaceuticallyacceptable excipient, the proportion and nature of which are determinedby the properties of the selected compound of the invention, the chosenroute of administration, and standard pharmaceutical practice.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising: a compound of invention and a pharmaceuticallyacceptable excipient. One skilled in the art can readily select anamount, form, and route of administration depending upon the particularcharacteristics of the compound selected, the disorder or condition tobe treated, the stage of the disorder or condition, and other relevantcircumstances.

The pharmaceutical compositions of the present invention are prepared ina manner well known in the pharmaceutical art and include at least oneof the compounds of the invention as the active ingredient. The amountof a compound of the present invention may be varied depending upon itsparticular properties and may conveniently be between about 1% to about70% of the weight of the dosage form. The present pharmaceuticalcompositions are preferably formulated in a unit dosage form, eachdosage typically containing from about 0.5 mg to about 200 mg of thecompounds of the invention. The term “unit dosage form” refers to aphysically discrete unit, each unit containing a predetermined quantityof active ingredient, in association with a suitable pharmaceuticalexcipient, by which one or more is used throughout the dosing regimen toproduce the desired therapeutic effect.

In effecting treatment of a patient, a compound of the invention can beadministered in any form and route which makes the compoundbioavailable. The compounds of the invention can be administered by avariety of routes, including oral and parenteral routes, moreparticularly by inhalation, subcutaneously, intramuscularly,intravenously, transdermally, intranasally, rectally, vaginally,occularly, topically, sublingually, and buccally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, intraadiposally,and intrathecally. The pharmaceutical compositions of the invention maybe administered to the patient, for example, in the form of tablets,capsules, cachets, papers, lozenges, wafers, elixirs, ointments,transdermal patches, aerosols, inhalants, suppositories, solutions, andsuspensions.

The term “pharmaceutically acceptable excipient” refers to thosetypically used in preparing pharmaceutical compositions and should bepharmaceutically pure and non-toxic in the amounts used. They generallyare a solid, semi-solid, or liquid material which can serve as a vehicleor medium for the active ingredient or an aid to the storage,administration, or manufacture of the composition. Some examples ofpharmaceutically acceptable excipients are found in Remington'sPharmaceutical Sciences and the Handbook of Pharmaceutical Excipientsand include diluents, vehicles, carriers, ointment bases, binders,disintegrates, lubricants, glidants, sweetening agents, flavoringagents, gel bases, sustained release matrices, stabilizing agents,preservatives, solvents, suspending agents, buffers, emulsifiers, dyes,propellants, coating agents, and others.

In one particular variation, the pharmaceutical composition is adaptedfor oral administration, such as a tablet or a capsule or a liquidformulation, for example, a solution or suspension, adapted for oraladministration. In still another particular variation, thepharmaceutical composition is a liquid formulation adapted forparenteral administration.

In another embodiment, the invention provides methods of treating adisease, disorder or condition associated with JAK. The methods compriseadministering to a patient in need thereof an effective amount of acompound of the invention. In another embodiment, the invention providesa method of inhibiting a JAK, comprising administering a compound of theinvention to a patient in order to inhibit the JAK pathway in vivo. In afurther embodiment, the invention provides a method of inhibiting a JAK,comprising administering a first compound to a subject that is convertedin vivo to a compound of the invention.

In another embodiment, compounds of the invention are provided for useas a medicament. The invention also provides the use of compounds of theinvention for the manufacture of a medicament to a treat disease,disorder or condition associated with JAK as described herein.

As used herein, the terms “condition,” “disorder,” and “disease” relateto any unhealthy or abnormal state. The phrase “disease, disorder orcondition associated with JAK” includes any disease, disorder orcondition in which the inhibition of JAK provides a therapeutic benefit,such as those characterized by abnormal JAK/STAT signaling, includingproliferative disorders, cardiac disorders, neurodegenerative disorders,autoimmune disorders, organ transplant, inflammatory disorders,immunological disorders, and allergic conditions, food allergies, atopicdermatitis and rhinitis. Where general terms are used herein to describeconditions associated with JAK it is understood that the morespecifically described conditions mentioned in the various diagnosticmanuals and other materials are included within the scope of thisinvention. For example, it is understood that proliferative disordersinclude cancer. Furthermore, for example, it is understood arthritis ispresently categorized into several more specific disorders, such asosteoarthritis and rheumatoid arthritis, and others, and all of whichare contemplated by the invention. Another example is systematicinflammatory response syndrome, which describes inflammation eventsassociated with sepsis, pancreatitis, multiple trauma, lacerations,brain injury or surgery, hemorrhagic shock, immune-mediated organinjuries, and others, all of which are contemplated by the invention.

The terms “treat,” “treatment,” and “treating” include improvement ofthe disease, disorder or condition described herein. Also, it isrecognized that one skilled in the art may affect the condition bytreating a patient presently afflicted with the disease, disorder orcondition by prophylactically treating a patient believed to besusceptible to the condition with an effective amount of a compound ofinvention. Thus, the terms “treat,” “treatment,” and “treating” includeall processes which may slow, interrupt, arrest, control, or stop theprogression of the diseases, disorders or conditions described herein,but do not necessarily indicate a total elimination of all symptoms or acure. Thus, the use of such terms is intended to include prophylacticand therapeutic treatment of any particular disease, disorder orcondition.

The terms “subject” and “patient” are used interchangeably and includehumans and non-human animals, for example, mammals, such as mice, rats,guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs.The terms also include birds, fish, reptiles, amphibians, and the like.It is understood that a more particular subject or patient is a human.Also, more particular subjects or patients are non-human mammals, suchas mice, rats, and dogs.

As used herein, the term “effective amount” refers to the amount ofcompound of the invention which treats, upon single or multiple doseadministration, a patient suffering from the disease, disorder orcondition associated with JAK. An effective amount can be readilydetermined by the attending diagnostician, as one skilled in the art, bythe use of known techniques and by observing results obtained underanalogous circumstances. In determining the effective amount, the dose,a number of factors are considered by the attending diagnostician,including, but not limited to: the species of patient; its size, age,and general health; the specific condition, disorder, or diseaseinvolved; the degree of or involvement or the severity of the condition,disorder, or disease, the response of the individual patient; theparticular compound administered; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; the use of concomitant medication; and otherrelevant circumstances. An effective amount of the present useinvention, including a compound of the invention, is expected to varyfrom about 0.1 milligram per kilogram of body weight per day (mg/kg/day)to about 20 mg/kg/day. Specific amounts can be determined by the skilledperson.

As noted above, the compounds of formula I may be used to treat adisease, disorder or condition associated with JAK, and such diseases,disorders or conditions generally relate to any unhealthy or abnormalstate in a subject for which the inhibition of JAK provides atherapeutic benefit. More particularly, such disorders, diseases, andconditions may involve the immune system and inflammation, includingType I hypersensitivity (allergic) reactions (allergic rhinitis,allergic asthma, and atopic dermatitis); autoimmune diseases (rheumatoidarthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis,immune thrombocytopenic purpura, amyotrophic lateral sclerosis, andorgan transplant rejection); inflammation of the lung (chronicobstructive pulmonary disease) and thrombosis. The compounds of formulaI may also be used to treat disorders, diseases, and conditions relatedto abnormal cell growth, including hematological malignancies, such asacute myeloid leukemia, B-cell chronic lymphocytic leukemia, B-celllymphoma (e.g., mantle cell lymphoma), and T-cell lymphoma (e.g.,peripheral T-cell lymphoma), as well as epithelial cancers (i.e.,carcinomas), such as lung cancer (small cell lung cancer and non-smallcell lung cancer), pancreatic cancer, and colon cancer.

In addition to the hematological malignancies and epithelial cancersnoted above, the compounds of formula I may also be used to treat othertypes of cancer, including leukemia (chronic myelogenous leukemia andchronic lymphocytic leukemia); breast cancer, genitourinary cancer, skincancer, bone cancer, prostate cancer, and liver cancer; brain cancer;cancer of the larynx, gall bladder, rectum, parathyroid, thyroid,adrenal, neural tissue, bladder, head, neck, stomach, bronchi, andkidneys; basal cell carcinoma, squamous cell carcinoma, metastatic skincarcinoma, osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, andKaposi's sarcoma; myeloma, giant cell tumor, islet cell tumor, acute andchronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma,medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinalganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitustumor, Wilms' tumor, seminoma, ovarian tumor, leiomyomater tumor,cervical dysplasia, neuroblastoma, retinoblastoma, myelodysplasticsyndrome, rhabdomyosarcoma, astrocytoma, non-Hodgkin's lymphoma,malignant hypercalcemia, polycythermia vera, adenocarcinoma,glioblastoma multiforma, glioma, lymphomas, and malignant melanomas,among others.

In addition to cancer, the compounds of formula I may also be used totreat other diseases related to abnormal cell growth, includingnon-malignant proliferative diseases such as benign prostatichypertrophy, restinosis, hyperplasia, synovial proliferation disorder,retinopathy or other neovascular disorders of the eye, among others.

The compounds of formula I may also be used to treat autoimmunedisorders in addition to those listed above. Such disorders, diseases,and conditions include Crohns disease, dermatomyositis, diabetesmellitus type 1, Goodpasture's syndrome, Graves' disease, Guillain-Barrésyndrome, Hashimoto's disease, mixed connective tissue damage,myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia,polymyositis, primary biliary cirrhosis, Sjögren's syndrome, temporalarteritis, ulcerative colitis, vasculitis, and Wegener's granulomatosis,among others.

Furthermore, compounds of formula I may be used to treat inflammatorydisorders including asthma, chronic inflammation, chronic prostatitis,glomerulonephritis, hypersensitivities, inflammatory bowel diseases(ulcerative colitis in addition to Crohn's disease), pelvic inflammatorydisease, reperfusion injury, transplant rejection, vasculitis, andsystemtic inflammatory response syndrome.

The compounds of formula I may also be used to treat specific diseasesthat may fall within one or more general disorders described above,including arthritis. In addition to rheumatoid arthritis, Sjögren'ssyndrome, systemic lupus erythematosus, SLE in children and adolescents,compounds of formula I may also be used to treat other arthritisdiseases, including ankylosing spondylitis, avascular necrosis, Bechet'sdisease, bursitis, calcium pyrophosphate dihyrate crystal depositiondisease (pseudo gout), carpal tunnel syndrome, Ehlers-Danlos syndrome,fibromyalgia, Fifth disease, giant cell arteritis, gout, juveniledermatomyositis, juvenile rheumatoid arthritis, juvenilespondyloarthopathy, Lyme disease, Marfan syndrome, myositis,osteoarthritis, osteogenesis imperfect, osteoporosis, Paget's disease,psoriatic arthritis, Raynaud's phenomenon, reactive arthritis, reflexsympathetic dystrophy syndrome, scleroderma, spinal stenosis, Still'sdisease, and tendinitis, among others.

The claimed and disclosed compounds may be combined with one or moreother pharmacologically active compounds or therapies for the treatmentof one or more diseases, disorders or conditions associated with JAK,including diseases, disorders or conditions involving the immune system,inflammation, and abnormal cell growth. For example, compounds offormula I, which include compounds specifically named in thespecification and claims, and their pharmaceutically acceptablecomplexes, salts, solvates and hydrates, may be administeredsimultaneously, sequentially or separately in combination with one ormore compounds or therapies for treating arthritis, including rheumatoidarthritis and osteoarthritis, or for treating cancer, includinghematological malignancies, such as acute myeloid leukemia, B-cellchronic lymphocytic leukemia, B-cell lymphoma, and T-cell lymphoma, andcarcinomas, such as lung cancer, pancreatic cancer, and colon cancer.Such combinations may offer significant therapeutic advantages,including fewer side effects, improved ability to treat underservedpatient populations, or synergistic activity.

For example, when used to treat arthritis, the compounds of formula Imay be combined with one or more nonsteroidal anti-inflammatory drugs(NSAIDs), analgesics, corticosteroids, biological response modifiers,and protein-A immunoadsorption therapy. Alternatively or additionally,when treating rheumatoid arthritis, the compounds of formula I may becombined with one or more disease modifying antirheumatic drugs(DMARDs), and when treating osteoarthritis, the compounds of formula Imay be combined with one or more osteoporosis agents.

Representative NSAIDs include apazone, aspirin, celecoxib, diclofenac(with and without misoprostol), diflunisal, etodolac, fenoprofen,flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium,mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin,phenylbutazone, piroxicam, choline and magnesium salicylates, salsalate,and sulindac. Representative analgesics include acetaminophen andmorphine sulfate, as well as codeine, hydrocodone, oxycodone,propoxyphene, and tramadol, all with or without acetaminophen.Representative corticosteroids include betamethasone, cortisone acetate,dexamethasone, hydrocortisone, methylprednisolone, prednisolone, andprednisone. Representative biological response modifiers include TNF-αinhibitors, such as adalimumab, etanercept, and infliximab; selectiveB-cell inhibitors, such as rituximab; IL-1 inhibitors, such as anakinra,and selective costimulation modulators, such as abatacept.

Representative DMARDs include auranofin (oral gold), azathioprine,chlorambucil, cyclophosamide, cyclosporine, gold sodium thiomalate(injectable gold), hydroxychloroquine, leflunomide, methotrexate,minocycline, myophenolate mofetil, penicillamine, and sulfasalazine.Representative osteoporosis agents include bisphosphonates, such asalendronate, ibandronate, risedronate, and zoledronic acid; selectiveestrogen receptor modulators, such as droloxifene, lasofoxifene, andraloxifene; hormones, such as calcitonin, estrogens, and parathyroidhormone; and immunosuppressant agents such as azathioprine,cyclosporine, and rapamycin.

Particularly useful combinations for treating rheumatoid arthritisinclude a compound of formula I and methotrexate, either alone, or incombination with one or more biological response modifiers, such aslefluonomide, etanercept, adalimumab, and infliximab.

For the treatment of thrombis and restensosis, the compounds of formulaI may be combined with one or more cardiovascular agents such as calciumchannel blockers, statins, fibrates, beta-blockers, ACE inhibitors, andplatelet aggregation inhibitors.

The compounds of formula I may also be combined with one or morecompounds or therapies for treating cancer. These includechemotherapeutic agents (i.e., cytotoxic or antineoplastic agents) suchas alkylating agents, antibiotics, antimetabolic agents, plant-derivedagents, and topoisomerase inhibitors, as well as molecularly targeteddrugs which block the growth and spread of cancer by interfering withspecific molecules involved in tumor growth and progression. Molecularlytargeted drugs include both small molecules and biologics.

Representative alkylating agents include bischloroethylamines (nitrogenmustards, e.g., chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, and uracil mustard); aziridines (e.g.,thiotepa); alkyl alkone sulfonates (e.g., busulfan); nitrosoureas (e.g.,carmustine, lomustine, and streptozocin); nonclassical alkylating agents(e.g., altretamine, dacarbazine, and procarbazine); and platinumcompounds (e.g., carboplatin, cisplatin, nedaplatin, oxaliplatin,satraplatin, and triplatin tetranitrate).

Representative antibiotic agents include anthracyclines (e.g.,aclarubicin, amrubicin, daunorubicin, doxorubicin, epirubicin,idarubicin, pirarubicin, valrubicin, and zorubicin); anthracenediones(e.g., mitoxantrone and pixantrone); and streptomyces (e.g.,actinomycin, bleomycin, dactinomycin, mitomycin C, and plicamycin).

Representative antimetabolic agents include dihydrofolate reductaseinhibitors (e.g., aminopterin, methotrexate, and pemetrexed); hymidylatesynthase inhibitors (e.g., raltitrexed and pemetrexed); folinic acid(e.g., leucovorin); adenosine deaminase inhibitors (e.g., pentostatin);halogenated/ribonucleotide reductase inhibitors (e.g., cladribine,clofarabine, and fludarabine); thiopurines (e.g., thioguanine andmercaptopurine); thymidylate synthase inhibitors (e.g., fluorouracil,capecitabine, tegafur, carmofur, and floxuridine); DNA polymeraseinhibitors (e.g., cytarabine); ribonucleotide reductase inhibitors(e.g., gemcitabine); hypomethylating agent (e.g., azacitidine anddecitabine); and ribonucleotide reductase inhibitor (e.g., hydroxyurea);and an asparagine depleter (e.g., asparaginase)

Representative plant-derived agents include vinca alkaloids (e.g.,vincristine, vinblastine, vindesine, vinzolidine, and vinorelbine),podophyllotoxins (e.g., etoposide and teniposide), and taxanes (e.g.,docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel).

Representative type I topoisomerase inhibitors include camptothecins,such as belotecan, irinotecan, rubitecan, and topotecan. Representativetype II topoisomerase inhibitors include amsacrine, etoposide, etoposidephosphate, and teniposide, which are derivatives of epipodophyllotoxins.

Molecularly targeted therapies include biologic agents such as cytokinesand other immune-regulating agents. Useful cytokines includeinterleukin-2 (IL-2, aldesleukin), interleukin 4 (IL-4), interleukin 12(IL-12), and interferon, which includes more than 23 related subtypes.Other cytokines include granulocyte colony stimulating factor (CSF)(filgrastim) and granulocyte macrophage CSF (sargramostim). Otherimmuno-modulating agents include bacillus Calmette-Guerin, levamisole,and octreotide; monoclonal antibodies against tumor antigens, such astrastruzumab and rituximab; and cancer vaccines, which induce an immuneresponse to tumors.

In addition, molecularly targeted drugs that interfere with specificmolecules involved in tumor growth and progression include inhibitors ofepidermal growth factor (EGF), transforming growth factor-alpha(TGF_(α), TGF_(β), heregulin, insulin-like growth factor (IGF),fibroblast growth factor (FGF), keratinocyte growth factor (KGF), colonystimulating factor (CSF), erythropoietin (EPO), interleukin-2 (IL-2),nerve growth factor (NGF), platelet-derived growth factor (PDGF),hetaptocyte growth factor (HGF), vascular endothelial growth factor(VEGF), angiopoietin, epidermal growth factor receptor (EGFR), humanepidermal growth factor receptor 2 (HER2), HER4, insulin-like growthfactor 1 receptor (IGF1R), IGF2R, fibroblast growth factor 1 receptor(FGF1R), FGF2R, FGF3R, FGF4R, vascular endothelial growth factorreceptor (VEGFR), tyrosine kinase with immunoglobulin-like and epidermalgrowth factor-like domains 2 (Tie-2), platelet-derived growth factorreceptor (PDGFR), Abl, Bcr-Abl, Raf, FMS-like tyrosine kinase 3 (FLT3),c-Kit, Src, protein kinase c (PKC), tropomyosin receptor kinase (Trk),Ret, mammalian target of rapamycin (mTOR), Aurora kinase, polo-likekinase (PLK), mitogen activated protein kinase (MEK),mesenchymal-epithelial transition factor (c-MET), cyclin-dependantkinase (CDK), Akt, extracellular signal-regulated kinases (ERK),poly(ADP) ribose polymerase (PARP), and the like.

Specific molecularly targeted drugs include selective estrogen receptormodulators, such as tamoxifen, toremifene, fulvestrant, and raloxifene;antiandrogens, such as bicalutamide, nilutamide, megestrol, andflutamide; and aromatase inhibitors, such as exemestane, anastrozole,and letrozole. Other specific molecularly targeted drugs include agentswhich inhibit signal transduction, such as imatinib, dasatinib,nilotinib, trastuzumab, gefitinib, erlotinib, cetuximab, lapatinib,panitumumab, and temsirolimus; agents that induce apoptosis, such asbortezomib; agents that block angiogenesis, such as bevacizumab,sorafenib, and sunitinib; agents that help the immune system destroycancel cells, such as rituximab and alemtuzumab; and monoclonalantibodies which deliver toxic molecules to cancer cells, such asgemtuzumab ozogamicin, tositumomab, 131I-tositumoab, and ibritumomabtiuxetan.

The invention also provides an article of manufacture, which comprisesat least one compound of the invention and a label. The label mayinclude information about the manufacturer, doses, conditions to betreated, and the use of the compound or pharmaceutical composition.

In another embodiment the invention provides a kit, which comprises atleast one compound of the invention, a label, and apparatus foradministration. The apparatus may include mixing vials, liquids forforming solutions or suspensions, tubing, syringes, and the like.

Biological Activity: JAK Inhibition

A compound's ability to inhibit JAK activity may be assessed using avariety of methods, including in vitro and in vivo assays. The followingin vitro assays measure a test compound's ability to inhibit JAK2- andJAK3-mediated phosphorylation of FAM-labeled JAK-specific substrates.

Purified JAK2 and JAK3 proteins were purchased from Invitrogen. JAK2 andJAK3 inhibition is determined using a black 384-well-plate format inbuffer containing 50 mM HEPES, 10 mM NaCl, 10 mM MgCl₂, 0.2 mM EDTA,0.01% EDA (Brij® 35), 1 mM DTT, 0.1 mg/mL BSA at pH 7.3. Each testcompound is prepared in DMSO using 2-fold serial dilutions for 11 datapoints and is added to the buffer so that each dilution contains 3%DMSO.

Assay for JAK2 Inhibition

To each well is added 2 μL of 3 μM 5FAM-KKKKEEIYFFFG-NH₂ and 45 μM ATP(in buffer), 2 μL of diluted test compound (3% DMSO in medium), and 2 μLof 0.6 nM JAK2 in buffer. The reaction mixture is incubated at roomtemperature for 60 min and is quenched by adding 50 mM HEPeX, 30 mMEDTA, and 0.1% Tx-100 (pH 7.3). To quantify the fluorescent-labeledsubstrate and product following reaction, the test plate is loaded on aCaliper LC-3000, which measures percent of conversion bymicrofluidic-based separation.

Assay for JAK3 Inhibition

To each well is added 2 μL of 3 μM 5FAM-KKKKEEIYFFFG-NH₂ and 15 μM ATP(in buffer), 2 μL of diluted test compound (3% DMSO in medium), and 2 μLof 1.2 nM JAK3 in buffer. The reaction mixture is incubated at roomtemperature for 60 min and is quenched by adding 50 mM HEPES, 30 mMEDTA, and 0.1% Tx-100 (pH 7.3). To quantify the fluorescent-labeledsubstrate and product following reaction, the test plate is loaded on aCaliper LC-3000, which measures percent of conversion bymicrofluidic-based separation.

Corresponding IC₅₀ values are calculated by non-linear curve fitting ofthe compound concentrations and percent of inhibition to the standardIC₅₀ equation.

EXAMPLES

The present invention is further illustrated by the following examplesand preparations. The examples and preparations do not limit the scopeof the invention in any way. ¹H Nuclear magnetic resonance (NMR) spectrawere obtained for many of the compounds in the following examples.Characteristic chemical shifts (δ) are given in parts-per-milliondownfield from tetramethylsilane using conventional abbreviations fordesignation of major peaks, including s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), and br (broad). The followingabbreviations are used for common solvents: CDCl₃ (deuterochloroform),DMSO-d₆ (deuterodimethylsulfoxide), CD₃OD (deuteromethanol), and THF-d₈(deuterotetrahydrofuran). The mass spectra ([M+H]) were recorded usingeither electrospray ionization (ESI) or atmospheric pressure chemicalionization (APCI).

Where indicated, products of certain preparations and examples arepurified by mass-triggered HPLC (Pump: Waters™ 2525; MS: ZQ™; Software:MassLynx™), flash chromatography or preparative thin layerchromatography (TLC). Preparative HPLC was carried out using eitheracidic or basic conditions. Acid conditions are typically gradients inSolvent A: water with 0.05% TFA and Solvent B: acetonitrile with 0.035%TFA; basic conditions are gradients in Solvent A: 10 nM NH₄HCO₃ in waterand Solvent B: 10 nM NH₄HCO₃ in 20/80 (v/v) water/acetonitrile. Thementioned preparative HPLC conditions use acidic conditions unlessindicated as basic. Preparative TLC is typically carried out on silicagel 60 F₂₅₄ plates. After isolation by chromatography, the solvent isremoved and the product is obtained by drying in a centrifugalevaporator (e.g., GeneVac™), rotary evaporator, evacuated flask, etc.Reactions in an inert (e.g., nitrogen) or reactive (e.g., H₂) atmosphereare typically carried out at a pressure of about 1 atmosphere (14.7psi).

Many of the abbreviations used in the examples are listed in Table 1,above. Abbreviations which are not listed in Table 1 have their usualmeanings unless indicated otherwise in the specification.

PREPARATION A: Methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate

Methyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate (500 mg, 2.84 mmol) andhexamethylenetetramine (796 mg, 5.68 mmol) were combined in water (8 mL)and glacial acetic acid (16 mL) and heated at 100° C. overnight thencooled to room temperature. The reaction mixture was extracted withethyl acetate and the organics were dried over MgSO₄ and concentrated invacuo to give a residue. Purification of the residue by silica gelchromatography (50% EtOAc/Hexanes) gave the title compound as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.57 (s, 1H), 8.48 (d,1H, J=4.8 Hz), 7.48 (d, 1H, J=4.8 Hz), 5.74 (d, 1H, J=6.8 Hz), 3.91 (s,3H), 2.78 (s, 3H). [M+H] found 205.

PREPARATION B: 1-tert-Butyl 4-methyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate

Methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (150 mg, 0.735mmol) was dissolved in DMF (5 mL) and triethylamine (0.31 mL, 2.20 mmol)was added to the solution. Then di-tert-butyl-dicarbonate (240 mg, 1.10mmol) was added and the mixture was allowed to stir for 3 h at roomtemperature. The solution was concentrated in vacuo. Purification bysilica gel chromatography (30% EtOAc/Hexanes) gave 165 mg of the titlecompound as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 10.16 (s, 1H), 8.64(s, 1H), 8.57 (d, 1H, J=5.0 Hz), 7.63 (d, 1H, J=5.1 Hz), 4.00 (s, 3H),1.72 (s, 9H). [M+H] found 305.

Example 1 tert-Butyl4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate

Methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (160 mg, 0.784mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (188 mg, 0.940mmol) were combined in MeOH (3 mL) and THF (3 mL) at 50° C. for 3 H.Then sodium borohydride (59 mg, 1.567 mmol) was added at roomtemperature and allowed to stir for 10 min. The mixture was quenchedwith water and extracted with ethyl acetate. The organics were driedover MgSO₄ and concentrated in vacuo to give methyl3-((1-(tert-butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate(60 mg) which was carried on to the next step. ¹H NMR (400 MHz, CD₃OD) δ8.32 (d, 1H, J=5.1 Hz), 7.61-7.62 (m, 2H), 4.07-4.13 (m, 4H), 4.01 (s,3H), 2.81-2.84 (m, 3H), 1.96-1.98 (m, 2H), 1.45-1.47 (m, 2H), 1.45 (s,9H). [M+H] found 389.

Methyl3-((1-(tert-butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate(60 mg, 0.154 mmol) was stirred in MeOH (2 mL), 1N NaOH (3 mL), and THF(2 mL) for 16 h. Then 1N HCl was added dropwise until pH=5 and themixture diluted with water and extracted with ethyl acetate. Theorganics were separated, dried over MgSO₄ and concentrated in vacuo.Purification by basic prep HPLC eluting with 10% to 35% B in A gave 50mg3-((1-(tert-butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 11.84 (s, 1H), 8.21 (d, 1H, J=4.8 Hz),7.67 (s, 1H), 7.34 (d, 1H, J=4.8 Hz), 4.14 (m, 2H), 3.96 (m, 2H),3.04-3.09 (m, 1H), 2.77 (m, 2H), 2.02-2.03 (m, 2H), 1.42-1.43 (m, 2H),1.40 (s, 9H). [M+H] found 375.

3-((1-(tert-Butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid (35 mg, 0.093 mmol), HATU (71 mg, 0.187 mmol), and pyridine (0.023mL, 0.280 mmol) were stirred in DMF (3 mL) at room temperature for 2 h.The solution was concentrated in vacuo and purified via basic prep HPLCeluting with 10% to 35% B in A and gave 18 mg of the title compound as ayellow solid. ¹H NMR (400 MHz, CD₃OD) δ 7.59 (m, 1H), 7.39-7.49 (m, 1H),4.98 (d, 2H, J=1.5 Hz), 4.77-4.79 (m, 1H), 4.25-4.28 (m, 2H), 2.87-2.92(m, 2H), 1.91-1.94 (m, 2H), 1.78-1.90 (m, 2H), 1.48 (s, 9H). [M+H] found357.

Example 24-(piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one

tert-Butyl4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate(18 mg, 0.051 mmol) was dissolved in TFA (1 mL) and DCM (2 mL) andallowed to stir at room temperature for 15 min. The mixture wasconcentrated in vacuo and purified via preparative HPLC 10% to 40% B inA and gave 12 mg of the title compound as its TFA salt. ¹H NMR (400 MHz,CD₃OD) δ 8.71-8.72 (s, 1H), 8.42 (d, 1H, J=8.4 Hz), 7.62 (s, 1H),7.48-7.49 (m, 2H), 5.02 (s, 1H), 4.69-4.75 (m, 2H), 3.58-3.61 (m, 2H),3.19-3.26 (m, 2H), 2.33-2.39 (m, 2H), 2.10-2.15 (m, 2H). [M+H] found257.

Example 33-oxo-3-(4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)propanenitrile

4-(Piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one(34 mg, 0.133 mmol) and triethylamine (0.055 mL, 0.398 mmol) weredissolved in EtOH (4 mL) and cooled to 0° C. and allowed to stir for 10min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (29 mg, 0.159 mmol)dissolved in EtOH (1 mL) was added dropwise and the mixture was allowedto stir for 30 min at 0° C. The solution was concentrated in vacuo andpurified via preparative HPLC eluting with 10% to 40% B in A and gave 10mg of the title compound as its TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 7.60(m, 1H), 7.43 (m, 1H), 4.98 (s, 2H), 4.84-4.88 (m, 1H), 4.68-4.72 (m,1H), 3.89-3.95 (m, 3H), 3.33 (m, 1H), 2.80-2.88 (m, 1H), 1.86-2.05 (m,4H). [M+H] found 324.

Example 4 tert-butyl4-methyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate

1-tert-Butyl 4-methyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (71 mg, 0.233 mmol)was dissolved in DCM (5 mL) and tert-butyl4-amino-4-methylpiperidine-1-carboxylate (50 mg, 0.233 mmol) was addedto the solution and allowed to stir for 2 h at room temperature. Thensodium triacetoxyborohydride (148 mg, 0.700 mmol) was added and themixture was allowed to stir for 2 h at room temperature. The solutionwas quenched with water and extracted with DCM. The organics were driedover MgSO₄ and concentrated in vacuo. Purification by silica gelchromatography (70% EtOAc/Hexanes) gave 90 mg of 1-tert-butyl 4-methyl3-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate.[M+H] found 403.

1-tert-Butyl 4-methyl3-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate(90 mg, 0.179 mmol) was stirred in MeOH (2 mL), 1N NaOH (3 mL), and THF(2 mL) for 16 h. The mixture was concentrated in vacuo. Purification viabasic preparative HPLC 15% to 35% B in A gave 34 mg of341-(tert-butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid. [M+H] found 389.

3-((1-(tert-Butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid (34 mg, 0.088 mmol), HATU (67 mg, 0.175 mmol), and pyridine (0.021mL, 0.263 mmol) were stirred in DMF (3 mL) at room temperature for 2 h.The solution was concentrated in vacuo to give the title compound whichwas used without further purification.

Example 54-(4-methylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one

The crude3-((1-(tert-butoxycarbonyl)-4-methylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid obtained in Example 4 was dissolved in DCM (3 mL) and TFA (1 mL)and allowed to stir at room temperature for 1 h. The solution wasconcentrated in vacuo and purified via preparative HPLC 5% to 20% B in Aand gave 21 mg of the title compound as its TFA salt. ¹H NMR (400 MHz,CD₃OD) δ 8.74 (s, 1H), 8.42 (m, 1H), 7.59 (m, 1H), 7.43 (m, 1H), 5.05(s, 2H), 3.29-3.33 (m, 2H), 3.22-3.23 (m, 2H), 2.93-2.97 (m, 2H),2.20-2.26 (m, 2H), 3.17 (s, 3H). [M+H] found 271.

Example 63-(4-methyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)-3-oxopropanenitrile

4-(4-Methylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one(21 mg, 0.078 mmol) and triethylamine (0.032 mL, 0.233 mmol) weredissolved in EtOH (4 mL) and cooled to 0° C. and allowed to stir for 10min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (17 mg, 0.093 mmol)dissolved in EtOH (1 mL) was added dropwise and the mixture was allowedto stir for 30 min at 0° C. The solution was concentrated in vacuo andpurified via preparative HPLC 10% to 40% B in A and gave 13 mg of thetitle compound as its TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 7.61 (m, 1H),7.43 (m, 1H), 5.08 (s, 2H), 3.90 (m, 2H), 3.72 (m, 1H), 3.61-3.62 (m,1H), 3.51-3.52 (m, 2H), 2.65-2.69 (m, 1H), 2.51-2.57 (m, 1H), 2.22-2.26(m, 1H), 2.10-2.12 (m, 1H), 1.66 (s, 3H). [M+H] found 338.

Example 7 tert-butyl4-ethyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate

1-tert-Butyl 4-methyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (211 mg, 0.692mmol) was dissolved in MeOH (10 mL) and tert-butyl4-amino-4-ethylpiperidine-1-carboxylate (158 mg, 0.692 mmol) were addedfollowed by 2 drops of acetic acid. The solution was allowed to stir atroom temperature for 2 h. Then sodium cyanoborohydride (44 mg, 0.692mmol) was added over the course of 6 h at room temperature. The solutionwas quenched with water and extracted with ethyl acetate. The organicswere dried over MgSO₄ and concentrated in vacuo. Purification by silicagel chromatography (70% EtOAc/Hexanes) gave 127 mg of 1-tert-butyl4-methyl3-((1-(tert-butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate.[M+H] found 417.

1-tert-Butyl 4-methyl3-((1-(tert-butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate(123 mg, 0.238 mmol) was stirred in MeOH (3 mL), 1N NaOH (3 mL), and THF(2 mL) for 16 h. The mixture was concentrated in vacuo. Purification viabasic prep HPLC 20% to 50% B in A gave 60 mg of3-(1-(tert-butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, 1H, J=4.8 Hz), 7.68 (s, 1H),7.52 (d, 1H, J=5.1 Hz), 4.31 (s, 2H), 3.95-4.01 (m, 1H), 2.03 (q, 2H,J=7.6 Hz), 1.92-1.94 (m, 4H), 1.47 (s, 9H), 1.46 (m, 2H), 1.07 (t, 1H,J=7.3 Hz). [M+H] found 403.

3-((1-(tert-Butoxycarbonyl)-4-ethylpiperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid (50 mg, 0.124 mmol), HATU (94 mg, 0.248 mmol), and4-dimethylaminopyridine (46 mg, 0.373 mmol) were stirred in DMF (3 mL)at room temperature for 1 h. The solution was concentrated in vacuo togive the title compound which was used without further purification.

Example 84-(4-ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one

tert-Butyl4-ethyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate(50 mg, 0.124 mmol), HATU (94 mg, 0.248 mmol), and4-dimethylaminopyridine (46 mg, 0.373 mmol) were stirred in DMF (3 mL)at room temperature for 1 h. The solution was concentrated in vacuo anddissolved in DCM (3 mL) and TFA (1 mL) and allowed to stir at roomtemperature for 1 h. The solution was concentrated in vacuo and waspurified via preparative HPLC 10% to 30% B in A and gave 28 mg of thetitle compound as its TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 7.36 (m, 1H),7.27 (m, 1H), 5.04 (s, 2H), 3.22-3.34 (m, 2H), 3.19-3.21 (m, 2H),2.95-2.98 (m, 2H), 2.13-2.23 (m, 4H), 0.97 (t, 3H, J=7.6 Hz). [M+H]found 285.

Example 93-(4-ethyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)-3-oxopropanenitrile

4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one(25 mg, 0.088 mmol) and triethylamine (0.037 mL, 0.264 mmol) weredissolved in EtOH (3 mL) and cooled to 0° C. and allowed to stir for 10min. Then 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (19 mg, 0.106 mmol)dissolved in EtOH (1 mL) was added dropwise and the mixture was allowedto stir for 30 min at 0° C. The solution was concentrated in vacuo andpurified via preparative HPLC 10% to 50% B in A and gave 16 mg of thetitle compound as its TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 7.03 (m, 1H),6.86 (m, 1H), 4.53 (d, 2H, J=2.0 Hz), 3.08-3.11 (m, 2H), 2.93-2.94 (m,2H), 2.72-2.73 (m, 2H), 2.04-2.09 (m, 1H), 1.91-1.94 (m, 1H), 1.36-1.72(m, 4H), 0.35 (t, 3H, J=7.6 Hz). [M+H] found 352.

Example 104-(pentan-3-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one

Pentan-3-amine (18 mg, 0.21 mmol) was added to a solution of1-tert-butyl 4-methyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (40 mg, 0.13 mmol)in MeOH (3 mL) with AcOH (2 drops). After stirring for 90 min at rt,sodium cyanoborohydride (33 mg, 0.53 mmol) was added, and the reactionwas stirred for an additional 3 h. The mixture was quenched with sat.NaHCO₃ solution and extracted with ethyl acetate. The organics weredried over MgSO₄ and concentrated in vacuo to give 42 mg of crude1-tert-butyl 4-methyl3-((penatan-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylateas a clear oil which was used without further purification. [M+H] found376.

1-tert-Butyl 4-methyl3-((penatan-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate(42 mg, 0.11 mmol) was stirred in MeOH (3 mL) with 1N NaOH (1 mL) at 50°C. for 3 h. The reaction was cooled to rt, neutralized with 1N HCl, andconcentrated in vacuo. The residue was dissolved in DMF (3 mL). HATU (71mg, 0.187 mmol) was added, and the reaction stirred at rt for 2 h. Thesolution was concentrated in vacuo and purified by preparative HPLCeluting with a gradient of 15% to 70% Solvent B in Solvent A to give 16mg of the title compound as an off-white solid. ¹H NMR (400 MHz, CD₃OD)δ 8.33 (d, 1H, J=4.8 Hz), 7.38 (d, 1H, J=4.8 Hz), 7.18 (s, 1H), 4.76 (s,2H), 4.68-4.80 (m, 1H), 1.60-1.71 (m, 4H), 0.87 (s, 6H). [M+H] found244.

Example 114-(1-cyclopropyl-3-hydroxypropyl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one

3-Amino-3-cyclopropylpropan-1-ol (30 mg, 0.26 mmol) was added to asolution of 1-tert-butyl 4-methyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (39.6 mg, 0.13mmol) in MeOH (3 mL) with AcOH (2 drops). After stirring for 90 min atrt, sodium cyanoborohydride (33 mg, 0.53 mmol) was added, and thereaction was stirred for an additional 3 h. The mixture was quenchedwith sat. NaHCO₃ solution and extracted with ethyl acetate. The organicswere dried over MgSO₄ and concentrated in vacuo to give 50 mg of crude1-tert-butyl 4-methyl34(1-cyclopropyl-3-hydroxypropylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylateas a yellow oil which was used without further purification. [M+H] found404.

1-tert-Butyl 4-methyl3-((1-cyclopropyl-3-hydroxypropylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate(50 mg, 0.12 mmol) was stirred in MeOH (3 mL) with 1N NaOH (1 mL) at rtfor 16 h. The reaction was neutralized with 1N HCl and concentrated invacuo. The residue was dissolved in DMF (3 mL). HATU (47 mg, 0.12 mmol)was added, and the reaction stirred at room temperature for 2 h. Thesolution was concentrated in vacuo and purified by preparative HPLCeluting with a gradient of 15% to 70% Solvent B in Solvent A to give 16mg of the title compound as an off-white solid. ¹H NMR (400 MHz, CD₃OD)δ 8.34 (d, 1H, J=4.8 Hz), 7.35 (d, 1H, J=4.8 Hz), 7.28 (s, 1H), 5.10 (ABq, 2H, J=76.4, 16.8 Hz), 4.08-4.20 (m, 1H), 3.59 (t, 2H, J=6.4 Hz),2.02-2.14 (m, 2H), 1.17-1.30 (m, 1H), 0.73-0.79 (m, 1H), 0.42-0.54 (m,2H), 0.24-0.33 (m, 1H). [M+H] found 272.

Example 12 Tert-Butyl3-((5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)methyl)pyrrolidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (91 mg, 0.3 mmol)in MeOH (2 mL) was added AcOH (5 drops) and tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate (90 mg, 0.45 mmol). Afterstirring for 60 min at rt, the reaction mixture was cooled to 0° C.Sodium cyanoborohydride (57 mg, 0.9 mmol) was added, and the reactionmixture was stirred for an additional 3 h at rt. The mixture wasquenched with water and extracted with ethyl acetate. The combinedorganic layers washed with saturated NaHCO₃ and with brine, dried overNa₂SO₄, and concentrated in vacuo to give 125 mg of crude 1-tert-butyl4-methyl3-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylateas a colorless oil which was used without further purification. [M+H]found 489.40.

To a solution of 1-tert-butyl 4-methyl3-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate(70 mg, 0.143 mmol) in dioxane (2 mL) was added 1N LiOH (0.358 mL, 0.358mmol) at 0° C. and stirred for 4 h at rt. The reaction mixture wasextracted with ether and the aqueous layer was neutralized with 1N HCl,and concentrated in vacuo to afford3-(((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid as an off-white solid. [M+H] found 375.

3-(((1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)methylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid was dissolved in DMF (3 mL). HATU (158 mg, 0.417 mmol) and DMAP (40mg, 0.278 mmol) were added, and the reaction was stirred at rt for 2 h,concentrated in vacuo, and purified by preparative HPLC eluting with agradient of 30% to 50% Solvent B in Solvent A to give 14.5 mg of thetitle compound as a light brown oil. ¹H NMR (400 MHz, CD₃OD) δ 1.46 (br.s., 9H) 1.70-1.81 (m, 1H) 1.99-2.11 (m, 1H) 2.78 (dt, J=14.34, 7.11 Hz,1H) 3.11-3.22 (m, 1H) 3.32-3.36 (m, 1H) 3.47-3.57 (m, 2H) 3.72 (d,J=7.33 Hz, 1H) 3.76-3.89 (m, 1H) 5.09 (s, 2H) 7.38 (s, 1H) 7.51 (d,J=5.31 Hz, 1H) 8.42 (d, J=5.56 Hz, 1H). [M+H] found 357.

Example 134-(pyrrolidin-3-ylmethyl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridine-5(1H)-one

To a solution of tert-butyl3-((5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)methyl)pyrrolidine-1-carboxylate(10 mg, 0.03 mmol) in dioxane at 0° C. was added 4N HCl in dioxane(0.019 mL, 0.075 mmol) and the reaction mixture was stirred for 1 h togive a solid. The solid was filtered and dried to afford the titlecompound (8.0 mg) as its HCl salt. ¹H NMR (400 MHz, CD₃OD) δ 1.90 (br.s., 1H) 2.24 (br. s., 1H) 2.96 (br. s., 1H) 3.17 (br. s., 2H) 3.59 (d,J=5.05 Hz, 1H) 3.71-3.83 (m, 2H) 3.87 (br. s., 1H) 5.18 (br. s., 2H)7.64 (br. s., 1H) 7.80 (br. s., 1H) 8.55 (br. s., 1H). [M+H] found 257.

Example 14 tert-butyl3-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (304 mg, 1.00 mmol)in 9:1 MeOH-Acetic Acid (2 mL) at 0° C. was added tert-butyl3-aminopiperidine-1-carboxylate (300 mg, 1.50 mmol) and the reactionmixture was stirred at rt for 1 h. Sodium cyanotrihydroborate (314 mg,5.00 mmol) was added slowly portion wise and the reaction mixture wasstirred at rt over night, quenched with water, and extracted with ethylacetate. The combined organic layers were washed with saturated NaHCO₃and with brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by silica gel chromatography (30% to 70%Hexane-EtOAc) to give 307 mg of methyl 3-((1-(tert-butoxycarbonyl)piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate as acolorless oil. [M+H] found 389.

To a solution of methyl3-((1-(tert-butoxycarbonyl)piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate(315 mg, 0.811 mmol) in dioxane (5 mL) at 0° C. was added 1N LiOH (2.03mL, 2.03 mmol) and stirred for 4 h at rt. The reaction mixture waspartitioned between ether and water. The separated aqueous layer wasneutralized with 1N HCl, and concentrated in vacuo to afford3-((1-(tert-butoxycarbonyl)piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid as an off-white solid. [M+H] found 375.

3-((1-(tert-butoxycarbonyl)piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylicacid was dissolved in DMF (5 mL). HATU (914 mg, 2.4 mmol) and DMAP (196mg, 1.6 mmol) were added, and the reaction stirred at rt for 2 h. Thesolution was concentrated in vacuo and purified by preparative HPLCeluting with a gradient of 30% to 50% Solvent B in Solvent A to give 123mg of the title compound as a light yellow solid. ¹H NMR (400 MHz,CD₃OD) δ 1.48 (s, 9H) 1.59-1.70 (m, 1H) 1.88 (d, J=13.39 Hz, 1H)1.95-2.02 (m, 1H) 2.06 (dd, J=12.25, 3.92 Hz, 1H) 2.75 (br. s., 1H) 3.15(t, J=11.62 Hz, 1H) 4.04-4.20 (m, 2H) 4.51 (br. s., 1H) 4.93-5.14 (m,2H) 7.44 (s, 1H) 7.58 (d, J=5.31 Hz, 1H) 8.43 (d, J=5.56 Hz, 1H). [M+H]found 357.

Example 154-(piperidin-3-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one

To a solution of tert-butyl3-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate(10 mg, 0.028 mmol) in dioxane at 0° C. was added 4N HCl in dioxane(0.018 mL, 0.07 mmol) and the reaction mixture was stirred for 1 h togive a solid. The solid was filtered and dried to afford the titlecompound (5.6 mg) as its HCl salt. ¹H NMR (400 MHz, CD₃OD) δ 1.82-2.13(m, 2H) 2.13-2.31 (m, 2H) 3.02 (td, J=13.07, 2.91 Hz, 1H) 3.41 (d,J=1.77 Hz, 1H) 3.44-3.51 (m, 2H) 4.68-4.84 (m, 1H) 5.00-5.19 (m, 2H)7.59 (s, 1H) 7.73 (d, J=6.06 Hz, 1H) 8.52 (d, J=6.06 Hz, 1H)). [M+H]found 257.

Example 164-(4-ethyl-1-propionylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one

4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one(12 mg, 0.042 mmol), propionic acid (4 mg, 0.055 mmol),4-dimethylaminopyridine (10 mg, 0.084 mmol), and HATU (32 mg, 0.084mmol) were dissolved in DMF (3 mL) at room temperature and allowed tostir for 3 h. The solution was concentrated in vacuo and purified viapreparative HPLC 10% to 40% B in A and gave 4.6 mg of the title compoundas its TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (m, 1H), 7.41 (m, 1H),5.12 (s, 2H), 3.70-3.74 (m, 1H), 3.59-3.63 (m, 3H), 2.58-2.61 (m, 1H),2.41-2.43 (m, 3H), 2.21-2.30 (m, 4H), 1.11 (t, 3H, J=7.6 Hz), 0.94 (t,3H, J=7.6 Hz). [M+H] found 341.

Example 17 4-(4-ethyl-1-(pyrimidin-4-yl)piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one

4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one(10 mg, 0.035 mmol), triethylamine (0.049 mL, 0.352 mmol), and4-chloropyrimidine (8 mg, 0.070 mmol) were dissolved in DMF (1.5 mL) andheated under microwave irradiation at 140° C. for 30 min. The solutionwas concentrated in vacuo and purified via preparative HPLC 10% to 40% Bin A and gave 6.5 mg of the title compound as its TFA salt. ¹H NMR (400MHz, CD₃OD) δ 8.66 (s, 1H), 8.14 (dd, 1H, J=7.6, 1.3 Hz), 7.51 (s, 1H),7.37 (s, 1H), 7.11 (d, 1H, J=7.5 Hz), 5.14 (s, 2H), 4.27 (m, 1H), 4.11(m, 1H), 3.86-3.87 (m, 1H), 3.80-3.82 (m, 1H), 2.86 (m, 1H), 2.73 (m,1H), 2.38 (m, 1H), 2.24-2.31 (m, 4H), 0.99 (t, 3H, J=7.6 Hz). MS (ES)[M+H] found 363.

PREPARATION C: (S)-2-amino-1-(pyrrolidin-1-yl)butan-1-one

STEP A: (S)-tert-butyl 1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate

To a mixture of (S)-2-(tert-butoxycarbonylamino)butanoic acid (1.4 g,6.89 mmol), HATU (3.14 g, 8.27 mmol), and pyrrolidine (1.216 mL, 13.78mmol) in DCM (50 mL) was added Et₃N (1.920 mL, 13.78 mmol). The reactionmixture was stirred at room temperature for 5 h and then washed withsaturated aqueous NaHCO₃ and brine. The organics were dried over MgSO₄and concentrated. Purification by silica column chromatography(MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil(1.75 g, 99%). ¹H NMR (500 MHz, CDCl₃) δ 0.94 (t, J=7.57 Hz, 3H)1.34-1.48 (m, 9H),1.49-1.68 (m, 1H) 1.68-1.81 (m, 1H) 1.81-1.92 (m, 2H)1.92-2.03 (m, 2H) 3.34-3.47 (m, 2H) 3.52 (dt, J=12.08, 7.14 Hz, 1H) 3.65(dt, J=10.13, 6.65 Hz, 1H) 4.30-4.42 (m, 1H) 5.35 (d, J=8.30 Hz, 1H).

STEP B: (S)-2-amino-1-(pyrrolidin-1-yl)butan-1-one

(S)-tert-butyl 1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate (1.75 g,6.83 mmol) was stirred in 50% TFA/DCM (10 mL) for 1 h. The reactionmixture was concentrated and isolated as a clear oil, TFA salt.Purification by flash column chromatography (MeOH/DCM, 0-10%) affordedthe title compound as a white solid (free base, 0.85 g, 5.44 mmol, 79%).¹H NMR (500 MHz, CDCl₃) δ 1.02 (t, J=7.45 Hz, 3H) 1.78-2.01 (m, 6H)3.30-3.46 (m, 2H) 3.51 (dt, J=12.20, 7.32 Hz, 1H) 3.59 (dt, J=10.25,6.59 Hz, 1H) 4.14 (t, J=6.10 Hz, 1H) 8.38 (br. s., 3H).

Example 18(S)-4-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

STEP A: (S)-1-tert-butyl 3-methyl4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

A mixture of sodium triacetoxyborohydride (279 mg, 1.315 mmol) and(S)-2-amino-1-(pyrrolidin-1-yl)butan-1-one (123 mg, 0.789 mmol) in DCE(2 mL) was stirred at room temperature for 30 min. The reaction mixturewas cooled to 0° C. A solution of 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (200 mg, 0.657mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). Thereaction was stirred at 0° C. for 30 min and then at room temperaturefor 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%)afforded the title compound as a yellow oil (83 mg, 28.4%). [M+H] calc'dfor C₂₃H₃₂N₄O₅, 445; found, 445.5.

STEP B:(S)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To a 20 mL round bottom flask with a stirrer was added (S)-1-tert-butyl3-methyl4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate(88 mg, 0.198 mmol), MeOH (1 mL) and THF (1 mL). Aqueous NaOH (12N, 1mL) was added and the reaction mixture was stirred at 53° C. for 16 h.The solvent was removed and the resulting residue was further purifiedvia preparative mass trigger LC-MS (AcCN/H₂O, 1-50%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow oil (6 mg, 9.17%). [M+H] calc'd for C₁₇H₂₂N₄O₃, 331; found,331.6.

STEP C:(S)-4-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

Into a 8 mL scintillation vial equipped for stirring was added(S)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid (6 mg, 0.018 mmol). N,N-dimethylformamide (2 mL), HATU (8.29 mg,0.022 mmol) and 4-methylmorpholine (2.2 mg, 0.022 mmol) were added andthe solution was allowed to stir at room temperature for 1 h. Thesolvent was removed and the resulting residue was further purified viapreparative mass trigger LC-MS (AcCN/H₂O, 5-90%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow solid (2.8 mg, 49.4%). ¹H NMR (500 MHz, CD₃OD) δ 0.97 (t,J=7.32 Hz, 3H) 1.74-1.98 (m, 5H) 1.98-2.14 (m, 1H) 3.08-3.22 (m, 1H)3.37-3.47 (m, 1H) 3.65-3.77 (m, 1H) 4.07 (s, 1H) 5.05 (s, 2H) 5.62 (dd,J=8.54, 7.08 Hz, 1H) 7.11 (d, J=4.88 Hz, 1H) 7.80 (s, 1H) 8.29 (br. s.,1H). [M+H] calc'd for C₁₇H₂₀N₄O₂, 313; found, 313.6.

PREPARATION D: (R)-2-amino-1-(pyrrolidin-1-yl)butan-1-one

STEP A: (R)-tert-butyl 1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate

To a mixture of (R)-2-(tert-butoxycarbonylamino)butanoic acid (1.5 g,7.38 mmol), HATU (3.37 g, 8.86 mmol) and pyrrolidine (1.303 mL, 14.76mmol) in DCM (50 mL) was added Et₃N (2.057 mL, 14.76 mmol). The reactionmixture was stirred at room temperature for 5 h and then washed withsaturated aqueous NaHCO₃ and brine. The organics were dried over MgSO₄and concentrated. Purification by silica column chromatography(MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil (1.6g, 85%). ¹H NMR (500 MHz, CDCl₃) δ 0.88-1.04 (m, 3H) 1.38-1.48 (m, 9H)1.52-1.64 (m, 1H) 1.69-1.79 (m, 1H) 1.82-1.92 (m, 2H) 1.92-2.02 (m, 2H)3.36-3.47 (m, 2H) 3.53 (dt, J=12.08, 7.14 Hz, 1H) 3.65 (dt, J=10.01,6.47 Hz, 1H) 4.30-4.43 (m, 1H) 5.37 (d, J=8.30 Hz, 1H).

STEP B: (R)-2-amino-1-(pyrrolidin-1-yl)butan-1-one

(R)-tert-butyl 1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate (1.6 g, 6.24mmol) was stirred in 50% TFA/DCM (10 mL) for 1 h. The reaction mixturewas concentrated and isolated as a clear oil, TFA salt. Purification bysilica column chromatography (MeOH/DCM, 0-10%) afforded the titlecompound as a white solid (free base, 0.91 g, 5.82 mmol, 79%). ¹H NMR(400 MHz, CDCl₃) δ 1.03 (t, J=7.45 Hz, 3H) 1.78-2.03 (m, 6H) 3.29-3.46(m, 2H) 3.46-3.54 (m, 1H) 3.54-3.66 (m, 1H) 4.14 (t, J=6.19 Hz, 1H).

Example 19(R)-4-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

STEP A: (R)-1-tert-butyl 3-methyl4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

A mixture of sodium triacetoxyborohydride (237 mg, 1.116 mmol) and(R)-2-amino-1-(pyrrolidin-1-yl)butan-1-one (131 mg, 0.837 mmol) in DCE(2 mL) was stirred at room temperature for 30 min. The reaction mixturewas cooled to 0° C. A solution of 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (200 mg, 0.657mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). Thereaction was stirred at 0° C. for 30 min and then at room temperaturefor 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%)afforded the title compound as a yellow oil (260 mg, 93%). [M+H] calc'dfor C₂₃H₃₂N₄O₅, 445; found, 445.5.

STEP B:(R)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To a 20 mL round bottom flask with a stirrer was added (R)-1-tert-butyl3-methyl4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate(150 mg, 0.337 mmol), MeOH (1 mL) and THF (1 mL). Aqueous NaOH (12 N, 1mL) was added and the reaction mixture was stirred at 53° C. for 16 h.The solvent was removed and the resulting residue was further purifiedvia preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow oil (8.7 mg, 0.026 mmol, 7.80%). [M+H] calc'd forC₁₇H₂₂N₄O₃, 331; found, 331.6.

STEP C:(R)-4-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

To an 8 mL scintillation vial equipped for stirring was added(S)-4-((1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid (8.7 mg, 0.026 mmol). N,N-dimethylformamide (2 mL), HATU (12.02 mg,0.032 mmol) and 4-methylmorpholine (3.20 mg, 0.022 mmol) were added andthe solution was allowed to stir at room temperature for 1 h. Thesolvent was removed and the resulting residue was further purified viapreparative mass trigger LC-MS (AcCN/H₂O, 5-90%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow solid (1.6 mg, 19.5%). ¹H NMR (500 MHz, CD₃OD) δ 0.88-1.04(m, 3H) 1.75-1.98 (m, 4H) 1.98-2.05 (m, 2H) 3.43-3.50 (m, 3H) 3.50-3.57(m, 1H) 5.07 (s, 2H) 5.62 (dd, J=8.79, 6.83 Hz, 1H) 7.13 (d, J=4.88 Hz,1H) 7.81 (s, 1H) 8.28 (d, J=5.37 Hz, 1H). [M+H] calc'd for C₁₇H₂₀N₄O₂,313; found, 313.6.

PREPARATION E: (R)-2-amino-3-methyl-1-(pyrrolidin-1-yl)butan-1-one

STEP A: (R)-tert-butyl3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate

To a mixture of (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid(1.0 g, 4.60 mmol), HATU (2.1 g, 5.52 mmol) and pyrrolidine (0.812 mL,9.21 mmol) in DCM (30 mL) was added Et₃N (1.28 mL, 9.21 mmol). Thereaction mixture was stirred at room temperature for 5 h and then washedwith saturated aqueous NaHCO₃ and brine. The organics were dried overMgSO₄ and concentrated. Purification by silica column chromatography(MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil(1.18 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ 0.95 (d, J=18.95 Hz, 3H) 0.95(d, J=5.31 Hz, 3H) 1.30-1.53 (m, 9H) 1.77-2.07 (m, 5H) 3.33-3.59 (m, 3H)3.59-3.80 (m, 1H) 4.25 (dd, J=9.35, 6.57 Hz, 1H) 5.30 (d, J=9.09 Hz,1H).

STEP B: (R)-2-amino-3-methyl-1-(pyrrolidin-1-yl)butan-1-one

(R)-tert-butyl 1-oxo-1-(pyrrolidin-1-yl)butan-2-ylcarbamate (1.18 g,4.37 mmol) was stirred in 50% TFA/DCM (10 mL) for 1 h. The reactionmixture was concentrated and isolated as a clear oil, TFA salt.Purification by flash column chromatography (MeOH/DCM, 0-10%) affordedthe title compound as a white solid (free base, 0.69 g, 92%). ¹H NMR(400 MHz, CDCl₃) δ 1.08 (d, J=7.07 Hz, 3H) 1.06 (d, J=7.07 Hz, 3H)1.77-2.04 (m, 4H) 2.12-2.26 (m, 1H) 3.26-3.45 (m, 2H) 3.45-3.58 (m, 1H)3.63 (dt, J=9.98, 6.51 Hz, 1H) 4.01 (d, J=5.56 Hz, 1H).

Example 20(R)-4-(3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

STEP A: (R)-1-tert-butyl 3-methyl4-((3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and(R)-2-amino-3-methyl-1-(pyrrolidin-1-yl)butan-1-one (84 mg, 0.493 mmol)in DCE (2 mL) was stirred at room temperature for 30 min. The reactionmixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100 mg, 0.329mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). Thereaction was stirred at 0° C. for 30 min and then at room temperaturefor 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%)afforded the title compound as a yellow oil (128 mg, 85%). [M+H] calc'dfor C₂₄H₃₄N₄O₅, 459; found, 459.6.

STEP B:(R)-4-((3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To an 8 mL scintillation vial equipped for stirring was added(R)-1-tert-butyl 3-methyl4-((3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate(134 mg, 0.292 mmol). Aqueous NaOH (12N, 2 mL) and MeOH (1 mL) wereadded and the solution was stirred at 53° C. for 48 h. The reactionmixture was purified via preparative mass trigger LC-MS (AcCN/H₂O,5-90%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound as a yellow oil.

STEP C:(R)-4-(3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

In a manner similar to Step C of Example 19,(R)-4-((3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (133 mg, 0.351 mmol)and 4-methylmorpholine (35.5 mg, 0.351 mmol) and the resulting productwas purified via preparative mass trigger LC-MS (AcCN/H₂O, 1-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (28 mg, 29.4% from Step B startingmaterial). ¹H NMR (400 MHz, CD₃OD) δ 0.92 (d, J=6.57 Hz, 3H) 1.04 (d,J=6.32 Hz, 3H) 1.78-1.94 (m, 3H) 1.94-2.02 (m, 1H) 2.02 (s, 1H)2.45-2.65 (m, 1H) 3.38-3.56 (m, 2H) 3.61-3.79 (m, 2H) 5.04-5.15 (m, 1H)5.45 (d, J=11.12 Hz, 1H) 7.30 (d, J=5.56 Hz, 1H) 7.91 (s, 1H) 8.35 (d,J=5.56 Hz, 1H). [M+H] calc'd for C₁₈H₂₂N₄O₂, 327; found, 327.6.

PREPARATION F: (R)-2-amino-4-methyl-1-(pyrrolidin-1-yl)pentan-1-one

STEP A: (R)-tert-butyl4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-ylcarbamate

To a mixture of (R)-2-(tert-butoxycarbonylamino)-4-methylpentanoic acid(1.0 g, 4.32 mmol), HATU (1.97 g, 5.19 mmol) and pyrrolidine (0.76 mL,8.65 mmol) in DCM (30 mL) was added Et₃N (1.2 mL, 8.65 mmol). Thereaction mixture was stirred at room temperature for 5 h and then washedwith saturated aqueous NaHCO₃ and brine. The organics were dried overMgSO₄ and concentrated. Purification by silica column chromatography(MeOH/DCM, 0-10%) afforded the title compound as a light yellow oil(1.17 g, 95%).

STEP B: (R)-2-amino-4-methyl-1-(pyrrolidin-1-yl)pentan-1-one

(R)-tert-Butyl 4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-ylcarbamatewas stirred in 50% TFA/DCM (10 mL) for 1 h. The reaction mixture wasconcentrated and isolated as clear oil, TFA salt. Purification by flashcolumn chromatography (MeOH/DCM, 0-10%) afforded the title compound as awhite solid (free base, 0.71 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ 0.96 (t,J=6.57 Hz, 6H) 1.42-1.60 (m, 1H) 1.75-2.04 (m, 6H) 3.26-3.44 (m, 2H)3.45-3.56 (m, 1H) 3.61 (dt, J=9.85, 6.57 Hz, 1H) 4.15 (dd, J=8.84, 4.29Hz, 1H).

Example 21(R)-4-(4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-oneSTEP A: (R)-1-tert-butyl 3-methyl4-((4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and(R)-2-amino-4-methyl-1-(pyrrolidin-1-yl)pentan-1-one (91 mg, 0.493 mmol)in DCE (2 mL) was stirred at room temperature for 30 min. The reactionmixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100 mg, 0.329mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). Thereaction was stirred at 0° C. for 30 min and then at room temperaturefor 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%)afforded the title compound as a yellow oil (160 mg, 93%). [M+H] calc'dfor C₂₅H₃₆N₄O₅, 473; found, 473.7.

STEP B:(R)-4-((4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To an 8 mL scintillation vial equipped for stirring was added(R)-1-tert-butyl 3-methyl4-((4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate(160 mg, 0.339 mmol) under nitrogen. Aqueous NaOH (12N, 2 mL) and MeOH(1 mL) were added and the solution was stirred at 53° C. for 48 h. Thereaction mixture was purified via preparative mass trigger LC-MS(AcCN/H₂O, 5-90%). The fractions were collected, concentrated, and driedin vacuo to afford the title compound as yellow oil.

STEP C:(R)-4-(4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

In a manner similar to Step C of Example 19,(R)-4-((4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (133 mg, 0.351 mmol)and 4-methylmorpholine (35.5 mg, 0.351 mmol) and the resulting productwas purified via preparative mass trigger LC-MS (AcCN/H₂O, 1-50%). Thefractions were collected, concentrated and dried in vacuo to afford thetitle compound as a yellow oil (53 mg, 46% from Step B startingmaterial). ¹H NMR (400 MHz, CDCl₃) δ 0.96 (t, J=6.57 Hz, 6H) 1.42-1.60(m, 1H) 1.75-2.04 (m, 6H) 3.26-3.44 (m, 2H) 3.45-3.56 (m, 1H) 3.61 (dt,J=9.85, 6.57 Hz, 1H) 4.15 (dd, J=8.84, 4.29 Hz, 1H). [M+H] calc'd forC₁₉H₂₄N₄O₂, 341; found, 341.6.

PREPARATION G: (R)-2-amino-N-cyclopentyl-3-methylbutanamide

STEP A: (R)-tert-butyl1-(cyclopentylamino)-3-methyl-1-oxobutan-2-ylcarbamate

To a mixture of (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid(0.5 g, 2.301 mmol), HATU (1.05 g, 2.76 mmol) and cyclopentanamine(0.455 mL, 4.60 mmol) in DCM (20 mL) was added Et₃N (0.642 mL, 4.60mmol). The reaction mixture was stirred at room temperature for 5 h,washed with saturated aqueous NaHCO₃ and brine, dried over MgSO₄, andconcentrated. Purification by silica column chromatography (MeOH/DCM,0-10%) afforded the title compound (0.61 g, 94%).

STEP B: (R)-2-amino-N-cyclopentyl-3-methylbutanamide

(R)-tert-Butyl 1-(cyclopentylamino)-3-methyl-1-oxobutan-2-ylcarbamatewas stirred in 50% TFA/DCM (10 mL) for 1 h. The reaction mixture wasconcentrated and isolated as a clear oil, TFA salt. Purification byflash column chromatography (MeOH/DCM, 0-10%) afforded the titlecompound as a white solid (free base, 0.37 g, 92%). ¹H NMR (400 MHz,CDCl₃) δ 0.96-1.08 (m, 6H) 1.35-1.51 (m, 1H) 1.51-1.74 (m, 4H) 1.90 (td,J=12.82, 6.19 Hz, 3H) 2.08-2.23 (m, 1H) 3.82 (d, J=6.82 Hz, 1H)4.02-4.21 (m, 1H) 7.32-7.53 (m, 0H) 7.40 (d, J=7.07 Hz, 1H).

Example 22(R)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

STEP A: (R)-1-tert-butyl 3-methyl4-((1-(cyclopentylamino)-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and(R)-2-amino-N-cyclopentyl-3-methylbutanamide (68.1 mg, 0.370 mmol) inDCE (2 mL) was stirred at room temperature for 30 min. The reactionmixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol)in DCE (2 mL) was added, followed by acetic acid (1 drop). The reactionmixture was stirred at 0° C. for 30 min and then at room temperature for3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%)afforded the title compound as a yellow oil (105 mg, 90%). [M+H] calc'dfor C₂₅H₃₆N₄O₅, 473; found, 473.7.

STEP B:(R)-4-((1-(cyclopentylamino)-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To an 8 mL scintillation vial equipped for stirring was added(R)-1-tert-butyl 3-methyl4-((1-(cyclopentylamino)-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate(105 mg, 0.222 mmol) under nitrogen. Aqueous NaOH (12N, 2 mL) and MeOH(1 mL) were added and the solution was stirred at 53° C. for 48 h. Thereaction mixture was purified via preparative mass trigger LC-MS(AcCN/H₂O, 5-90%). The fractions were collected, concentrated, and driedin vacuo to afford the title compound as yellow oil.

STEP C:(R)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

In a manner similar to Step C of Example 19,(R)-4-((1-(cyclopentylamino)-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (101 mg, 0.267 mmol)and 4-methylmorpholine (27.0 mg, 0.267 mmol) and the resulting productwas purified via preparative mass trigger LC-MS (AcCN/H₂O, 1-50%). Thefractions were collected, concentrated and dried in vacuo to afford thetitle compound as a yellow oil (23 mg, 30% from Step B startingmaterial). ¹H NMR (400 MHz, CD₃OD) δ 0.99-1.04 (m, 3H) 1.04-1.08 (m, 3H)1.28-1.38 (m, 1H) 1.42-1.67 (m, 4H) 1.72 (br. s., 2H) 1.77-2.00 (m, 2H)2.79-2.90 (m, 1H) 4.02-4.21 (m, 2H) 5.12 (d, J=9.35 Hz, 1H) 7.78 (d,J=5.31 Hz, 1H) 7.93-8.08 (m, 1H) 8.63 (d, J=5.30 Hz, 1H). [M+H] calc'dfor C₁₉H₂₄N₄O₂, 341; found, 341.4.

PREPARATION H: (2R,3R)-2-amino-N-cyclopentyl-3-methylpentanamide

STEP A: tert-butyl(2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylcarbamate

To a mixture of (2R,3R)-2-(tert-butoxycarbonylamino)-3-methylpentanoicacid (0.5 g, 2.162 mmol, HATU (0.986 g, 2.59 mmol) and cyclopentanamine(0.427 mL, 4.32 mmol) in DCM (10 mL) was added Et₃N (0.603 mL, 4.32mmol). The reaction mixture was stirred at room temperature for 5 h andthen washed with saturated aqueous NaHCO₃ and brine. The organics weredried over MgSO₄ and concentrated. Purification by silica columnchromatography (MeOH/DCM, 0-10%) afforded the title compound (0.56 g,87%). ¹H NMR (400 MHz, CDCl₃) δ 0.82-0.89 (m, 3H) 0.92 (t, J=7.45 Hz,3H) 1.32-1.41 (m, 6H) 1.44 (s, 9H) 1.55-1.77 (m, 3H) 1.84-2.04 (m, 2H)2.99 (d, J=4.29 Hz, 1H) 3.96 (dd, J=8.72, 5.43 Hz, 1H) 4.21 (dt,J=13.89, 6.95 Hz, 1H) 5.02 (br. s., 1H) 5.93 (br. s., 1H).

STEP B: (2R,3R)-2-amino-N-cyclopentyl-3-methylpentanamide

A mixture of tert-butyl(2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylcarbamate and 50%TFA/DCM (10 mL) was stirred for 1 h. The reaction mixture wasconcentrated and isolated as a clear oil, TFA salt. Purification byflash column chromatography (MeOH/DCM, 0-10%) afforded the titlecompound as a white solid (free base, 0.34 g, 90%). Pure product by TLC(visualized by ninhydrin stain).

Example 23(2R,3R)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)pentanamide

STEP A: 1-tert-butyl 3-methyl4-(((2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and(2R,3R)-2-amino-N-cyclopentyl-3-methylpentanamide (48.9 mg, 0.246 mmol)in DCE (2 mL) was stirred at room temperature for 30 min. To thismixture was added 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246mmol). The reaction mixture was stirred at room temperature for 1 h andwas subsequently concentrated to afford the title compound as a crudeintermediate. [M+H] calc'd for C₂₆H₃₈N₄O₅, 487; found, 487.7.

STEP B:4-(((2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To crude 1-tert-butyl 3-methyl4-(((2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylatewas added MeOH (1 mL) and aqueous NaOH (12N, 2 mL). The reaction mixturewas stirred at 53° C. for 16 h and then purified via preparative masstrigger LC-MS (AcCN/H₂O, 5-90%). The fractions were collected,concentrated, and dried in vacuo to afford the title compound. [M+H]calc'd for C₂₀H₂₈N₄O₃, 373; found, 373.7.

STEP C:(2R,3R)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)pentanamide

In a manner similar to Step C of Example 19,4-(((2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (112 mg, 0.296 mmol)and 4-methylmorpholine (37.4 mg, 0.370 mmol) and the resulting productwas purified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (32 mg, 37% from Step A startingmaterial). ¹H NMR (400 MHz, CD₃OD) δ 0.61-0.72 (m, 2H) 0.90-1.06 (m, 5H)1.37-1.66 (m, 7H) 1.66-1.77 (m, 2H) 1.77-1.99 (m, 4H) 3.98-4.22 (m, 1H)4.85-4.97 (m, 2H) 5.21 (d, J=9.35 Hz, 1H). [M+H] calc'd for C₂₀H₂₆N₄O₂,355; found, 355.5.

Example 24(2R,3S)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)pentanamide

STEP A:(2R,3S)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3-methylpentanoicacid

To a 10 mL round bottom flask was added sodium triacetoxyborohydride(104 mg, 0.493 mmol), (2R,3S)-2-amino-3-methylpentanoic acid (43.1 mg,0.329 mmol), and DCM (2 mL). The mixture was stirred at room temperaturefor 30 min, after which was added 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol)in DCM (2 mL). The reaction was stirred at room temperature for 2 h andthen quenched with MeOH (3 drops). The mixture concentrated to affordthe title compound, which was used in the next step without furtherpurification. [M+H] calc'd for C₂₁H₂₉N₃O₆, 420; found, 420.6.

STEP B: 1-tert-butyl 3-methyl4-(((2R,3S)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

To(2R,3S)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3-methylpentanoicacid was added THF (2 mL), followed by HATU (94 mg, 0.246 mmol),cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg,0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford thetitle compound, which was used in the next step without furtherpurification. [M+H] calc'd for C₂₆H₃₈N₄O₅, 487; found, 487.7.

STEP C:4-(((2R,3S)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

Crude 1-tert-butyl 3-methyl4-(((2R,3S)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylatewas concentrated and re-dissolved in MeOH (1 mL). Aqueous NaOH (12N, 2mL) was added and the reaction mixture was stirred at 53° C. for 16 h.The product was purified via preparative mass trigger LC-MS (AcCN/H₂O,5-50%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound. [M+H] calc'd for C₂₀H₂₈N₄O₃, 373; found,373.7.

STEP D:(2R,3S)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)pentanamide

In a manner similar to Step C of Example 19,4-(((2R,3S)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (94 mg, 0.246 mmol)and 4-methylmorpholine (83 mg, 0.822 mmol) and the resulting product waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (6 mg, 10% from Step A startingmaterial). ¹H NMR (500 MHz, CD₃OD) δ 0.89 (d, J=6.35 Hz, 3H) 0.95-1.06(m, 3H) 1.15-1.26 (m, 1H) 1.35-1.45 (m, 1H) 1.45-1.63 (m, 4H) 1.70 (br.s., 1H) 1.81-2.02 (m, 2H) 2.10-2.19 (m, 1H) 2.28 (br. s., 1H) 3.34 (s,1H) 4.02-4.16 (m, 1H) 5.04-5.18 (m, 1H) 5.40-5.56 (m, 1H) 7.29 (d,J=5.37 Hz, 1H) 7.90 (s, 1H) 8.34 (d, J=5.37 Hz, 1H). [M+H] calc'd forC₂₀H₂₆N₄O₂, 355; found, 355.5.

Example 25(R)—N-cyclopentyl-2-cyclopropyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)acetamide

STEP A:(R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopropylaceticacid

To a 10 mL round bottom flask was added sodium triacetoxyborohydride(104 mg, 0.493 mmol), (R)-2-amino-2-cyclopropylacetic acid (37.8 mg,0.329 mmol), and DCM (2 mL). The reaction mixture was stirred at roomtemperature in for 30 min, after which was added 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol)in DCM (2 mL). The reaction was stirred at room temperature for 2 h andthen quenched with MeOH (3 drops). The mixture was concentrated toafford the title compound, which was used in the next step withoutfurther purification. [M+H] calc'd for C₂₀H₂₅N₃O₆, 404; found, 404.3.

STEP B: (R)-1-tert-butyl 3-methyl4-((2-(cyclopentylamino)-1-cyclopropyl-2-oxoethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

To(R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopropylaceticacid was added THF (2 mL), followed by HATU (94 mg, 0.246 mmol),cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg,0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford thetitle compound, which was used in the next step without furtherpurification. [M+H] calc'd for C₂₅H₃₄N₄O₅, 471; found, 471.5.

STEP C:(R)-4-((2-(cyclopentylamino)-1-cyclopropyl-2-oxoethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

Crude (R)-1-tert-butyl 3-methyl4-((2-(cyclopentylamino)-1-cyclopropyl-2-oxoethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylatewas concentrated and re-dissolved in MeOH (1 mL). Aqueous NaOH (12N, 2mL) was added and the reaction mixture was stirred at 53° C. for 16 h.The product was purified via preparative mass trigger LC-MS (AcCN/H₂O,5-50%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound. [M+H] calc'd for C₁₉H₂₄N₄O₃, 357; found,357.5.

STEP D:(R)—N-cyclopentyl-2-cyclopropyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)acetamide

In a manner similar to Step C of Example 19,(R)-4-((2-(cyclopentylamino)-1-cyclopropyl-2-oxoethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (94 mg, 0.246 mmol)and 4-methylmorpholine (83 mg, 0.822 mmol) and the resulting product waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (4.4 mg, 8% from Step A startingmaterial). ¹H NMR (500 MHz, CD₃OD) δ 0.38 (d, J=5.37 Hz, 1H) 0.73 (t,J=4.90 Hz, 1H) 0.82 (br. s., 1H) 1.45-1.57 (m, 2H) 1.60 (s, 2H) 1.73(br. s., 2H) 1.83-1.98 (m, 2H) 3.09-3.22 (m, 1H) 3.68-3.77 (m, 1H) 4.13(d, J=5.86 Hz, 1H) 5.48-5.58 (m, 2H) 7.29 (d, J=5.37 Hz, 1H) 7.84 (s,1H) 8.35 (br. s., 1H). [M+H] calc'd for C₁₉H₂₂N₄O₂, 339; found, 339.5.

Example 26(R)—N-cyclopentyl-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

STEP A:(R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3,3-dimethylbutanoicacid

To a 10 mL round bottom flask was added sodium triacetoxyborohydride(104 mg, 0.493 mmol), (R)-2-amino-3,3-dimethylbutanoic acid (43.1 mg,0.329 mmol) and DCM (2 mL). The reaction mixture were stirred at roomtemperature in for 30 min after which was added 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol)in DCM (2 mL). The reaction was stirred at room temperature for 2 h andthen quenched with MeOH (3 drops). The mixture was concentrated toafford the title compound, which was used in the next step withoutfurther purification. [M+H] calc'd for C₂₁H₂₉N₃O₆, 420; found, 420.3.

STEP B: (R)-1-tert-butyl 3-methyl4-((1-(cyclopentylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

To(R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3,3-dimethylbutanoicacid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine(70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). Thesuspension was stirred at 43° C. for 36 h to afford the title compound,which was used in the next step without further purification. [M+H]calc'd for C₂₆H₃₈N₄O₅, 487; found, 487.6.

STEP C:(R)-4-((1-(cyclopentylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

Crude (R)-1-tert-butyl 3-methyl4-((1-(cyclopentylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylatewas concentrated and was re-dissolved in MeOH (1 mL). Aqueous NaOH (12N,2 mL) was added and the reaction mixture was stirred at 53° C. for 16 h.The product was purified via preparative mass trigger LC-MS (AcCN/H₂O,5-50%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound. [M+H] calc'd for C₂₀H₂₈N₄O₃, 373; found,373.6.

STEP D:(R)—N-cyclopentyl-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

In a manner similar to Step C of Example 19,(R)-4-((1-(cyclopentylamino)-3,3-dimethyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (94 mg, 0.246 mmol)and 4-methylmorpholine (83 mg, 0.822 mmol), and the resulting productwas purified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (9.2 mg, 15.8% from Step A startingmaterial). ¹H NMR (400 MHz, CD₃OD) δ 1.16 (s, 9H) 1.36-1.65 (m, 4H)1.65-1.77 (m, 2H) 1.78-2.05 (m, 2H) 4.11 (t, J=6.82 Hz, 1H) 5.30-5.51(m, 2H) 5.51-5.69 (m, 1H) 7.13-7.31 (m, 1H) 7.25 (d, J=5.56 Hz, 1H) 7.87(s, 1H) 8.32 (d, J=5.31 Hz, 1H). [M+H] calc'd for C₂₀H₂₆N₄O₂, 355;found, 355.6.

Example 27(R)—N,2-dicyclopentyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)acetamide

STEP A:(R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopentylaceticacid

To a 10 mL round bottom flask was added sodium triacetoxyborohydride(104 mg, 0.493 mmol), (R)-2-amino-2-cyclopentylacetic acid (47.1 mg,0.329 mmol) and DCM (2 mL). The reaction mixture was stirred at roomtemperature for 30 min after which was added 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol)in DCM (2 mL). The reaction was stirred at room temperature for 2 h andthen quenched with MeOH (3 drops). The mixture was concentrated toafford the title compound, which was used in the next step withoutfurther purification. [M+H] calc'd for C₂₂H₂₉N₃O₆, 432; found, 432.4.

STEP B: (R)-1-tert-butyl 3-methyl4-((1-cyclopentyl-2-(cyclopentylamino)-2-oxoethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

To(R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-2-cyclopentylaceticacid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine(70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). Thesuspension was stirred at 43° C. for 36 h to afford the title compound,which was used in the next step without further purification. [M+H]calc'd for C₂₇H₃₈N₄O₅, 499; found, 499.6.

STEP C:(R)-4-((1-cyclopentyl-2-(cyclopentylamino)-2-oxoethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

Crude (R)-1-tert-butyl 3-methyl4-((1-cyclopentyl-2-(cyclopentylamino)-2-oxoethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylatewas concentrated and re-dissolved in MeOH (1 mL). Aqueous NaOH (12N, 2mL) was added and the reaction mixture was stirred at 53° C. for 16 h.The product was purified via preparative mass trigger LC-MS (AcCN/H₂O,5-50%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound. [M+H] calc'd for C₂₁H₂₈N₄O₃, 384; found,384.6.

STEP D:(R)—N,2-dicyclopentyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)acetamide

In a manner similar to Step C of Example 19,(R)-4-((1-cyclopentyl-2-(cyclopentylamino)-2-oxoethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (94 mg, 0.246 mmol)and 4-methylmorpholine (83 mg, 0.822 mmol), and the resulting productwas purified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (11 mg, 18.7% from Step A startingmaterial). ¹H NMR (400 MHz, CD₃OD) δ 1.22-1.34 (m, 1H) 1.34-1.45 (m, 2H)1.54-1.78 (m, 10H) 1.78-2.00 (m, 3H) 2.65-2.84 (m, 1H) 4.00-4.15 (m, 1H)5.08 (d, J=11.37 Hz, 1H) 5.21 (s, 1H) 5.47 (s, 1H) 7.12-7.36 (m, 1H)7.24 (d, J=5.31 Hz, 1H) 7.86 (s, 1H) 8.32 (d, J=5.31 Hz, 1H). [M+H]calc'd for C₂₁H₂₆N₄O₂, 367; found, 367.6.

Example 28(R)—N-cyclopentyl-4,4,4-trifluoro-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

STEP A:(R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-4,4,4-trifluorobutanoicacid

To a 10 mL round bottom flask was added sodium triacetoxyborohydride(104 mg, 0.493 mmol), 2-amino-4,4,4-trifluorobutanoic acid (51.6 mg,0.329 mmol) and DCM (2 mL). The reaction mixture was stirred for 30 minafter which was added 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol)in DCM (2 mL). The reaction was stirred at room temperature for 2 h andthen quenched with MeOH (3 drops). The mixture was concentrated toafford the title compound, which was used in the next step withoutfurther purification. [M+H] calc'd for C₁₉H₂₂F₃N₃O₆, 446; found, 446.5.

STEP B: (R)-1-tert-butyl 3-methyl4-((1-(cyclopentylamino)-4,4,4-trifluoro-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

To(R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-4,4,4-trifluorobutanoicacid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine(70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). Theresulting suspension was stirred at 43° C. for 36 h to afford the titlecompound, which was used in the next step without further purification.[M+H] calc'd for C₂₄H₃₁F₃N₄O₅, 513; found, 513.6.

STEP C:(R)-4-((1-(cyclopentylamino)-4,4,4-trifluoro-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

Crude (R)-1-tert-butyl 3-methyl4-((1-(cyclopentylamino)-4,4,4-trifluoro-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylatewas concentrated and re-dissolved in MeOH (1 mL). Aqueous NaOH (12N, 2mL) was added and the reaction mixture was stirred at 53° C. for 16 h.The product was purified via preparative mass trigger LC-MS (AcCN/H₂O,5-50%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound. [M+H] calc'd for C₁₈H₂₁F₃N₄O₃, 399; found,399.6.

STEP D:(R)—N-cyclopentyl-4,4,4-trifluoro-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

In a manner similar to Step C of Example 19,(R)-4-((1-(cyclopentylamino)-4,4,4-trifluoro-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (94 mg, 0.246 mmol)and 4-methylmorpholine (83 mg, 0.822 mmol) and the resulting product waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (4.5 mg, 7.2% from Step A startingmaterial). ¹H NMR (400 MHz, CD₃OD) δ 1.32-1.62 (m, 4H) 1.62-1.78 (m, 2H)1.82-2.05 (m, 2H) 2.87-3.07 (m, 1H) 3.07-3.21 (m, 1H) 4.10-4.24 (m, 1H)5.13 (d, J=19.20 Hz, 1H) 5.26 (d, J=18.95 Hz, 1H) 5.41 (dd, J=8.08, 5.31Hz, 1H) 7.24 (d, J=5.31 Hz, 1H) 7.90 (s, 1H) 8.36 (d, J=5.05 Hz, 1H).[M+H] calc'd for C₁₈H₁₉F₃N₄O₂, 381; found, 381.5.

PREPARATION I: (R)-2-amino-N-cyclopentyl-3-hydroxy-3-methylbutanamide

STEP A: (R)-tert-butyl1-(cyclopentylamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylcarbamate

To a mixture of(R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-methylbutanoic acid (0.5 g,2.144 mmol), HATU (0.978 g, 2.57 mmol) and cyclopentanamine (0.423 mL,4.29 mmol) in DCM (10 mL) was added Et₃N (0.598 mL, 4.29 mmol). Thereaction mixture was stirred at room temperature for 5 h and then washedwith saturated aqueous NaHCO₃ and brine. The organics were dried overMgSO₄, concentrated, and purified by silica column chromatography(MeOH/DCM, 0-10%) to afford the title compound (0.6 g, 93%).

STEP B: (R)-2-amino-N-cyclopentyl-3-hydroxy-3-methylbutanamide

A mixture of (R)-tert-butyl1-(cyclopentylamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylcarbamate and 50%TFA/DCM (10 mL) was stirred for 1 h. The resulting product wasconcentrated and isolated as clear oil, TFA salt. Purification by flashcolumn chromatography (MeOH/DCM, 0-10%) afforded the title compound as awhite solid (free base, 0.37 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.13(s, 3H) 1.23 (s, 3H) 1.40 (s, 2H) 1.44-1.69 (m, 4H) 1.73-2.01 (m, 2H)3.48 (s, 1H) 3.89-4.16 (m, 1H) 5.33 (s, 1H) 7.87-7.89 (m, 2H) 8.33 (d,J=7.33 Hz, 1H).

Example 29(R)—N-cyclopentyl-3-hydroxy-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

STEP A: (R)-1-tert-butyl 3-methyl4-((1-(cyclopentylamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

A mixture of sodium triacetoxyborohydride (104 mg, 0.493 mmol) and(R)-2-amino-N-cyclopentyl-3-hydroxy-3-methylbutanamide (49.4 mg, 0.246mmol) in DCE (2 mL) was stirred at room temperature for 30 min.1-tert-Butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (75 mg, 0.246 mmol)was added and the reaction mixture was stirred at room temperature for 1h. Following reaction, the mixture was concentrated to afford the titlecompound. [M+H] calc'd for C₂₅H₃₆N₄O₆, 489; found, 489.3.

STEP B:(R)-4-((1-(cyclopentylamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To (R)-1-tert-butyl 3-methyl4-((1-(cyclopentylamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylatewas added MeOH (1 mL) and aqueous NaOH (12N, 2 mL). The reaction mixturewas stirred at 53° C. for 16 h and the resulting product was purifiedvia preparative mass trigger LC-MS (AcCN/H₂O, 5-90%). The fractions werecollected, concentrated, and dried in vacuo to afford the titlecompound. [M+H] calc'd for C₁₉H₂₆N₄O₄, 375; found, 374.5.

STEP C:(R)—N-cyclopentyl-3-hydroxy-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

In a manner similar to Step C of Example 19,(R)-4-((1-(cyclopentylamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (112 mg, 0.296 mmol)and 4-methylmorpholine (37.4 mg, 0.370 mmol) and the resulting productwas purified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (6.5 mg, 7.4% from Step A startingmaterial). ¹H NMR (500 MHz, CD₃OD) δ 1.20 (s, 3H) 1.37-1.41 (m, 3H)1.41-1.79 (m, 5H) 1.85-2.00 (m, 3H) 4.19 (s, 1H) 5.14-5.26 (m, 1H) 5.35(s, 1H) 5.64-5.77 (m, 1H) 7.22 (d, J=5.37 Hz, 1H) 7.89 (s, 1H) 8.31 (d,J=5.37 Hz, 1H). [M+H] calc'd for C₁₉H₂₄N₄O₃, 357; found, 357.5.

PREPARATION J: (R)-2-amino-3-cyano-N-cyclopentylpropanamide

STEP A: (R)-tert-butyl3-cyano-1-(cyclopentylamino)-1-oxopropan-2-ylcarbamate

To a mixture of (R)-2-(tert-butoxycarbonylamino)-3-cyanopropanoic acid(0.5 g, 2.334 mmol), HATU (0.986 g, 2.59 mmol) and cyclopentanamine(0.461 mL, 4.67 mmol) in DCM (10 mL) was added Et₃N (0.651 mL, 4.67mmol). The reaction mixture was stirred at room temperature for 5 h andthen washed with saturated aqueous NaHCO₃ and brine. The organics weredried over MgSO₄ and concentrated. Purification by silica columnchromatography (MeOH/DCM, 0-10%) afforded the title compound (0.61 g,93%). ¹H NMR (400 MHz, CD₃OD) δ1.50 (s, 9H) 1.57-1.73 (m, 4H) 1.79-1.87(m, 3H) 1.89-2.02 (m, 1H) 2.05-2.19 (m, 3H) 2.76-2.95 (m, 1H) 3.87 (t,J=7.07 Hz, 1H).

STEP B: (R)-2-amino-3-cyano-N-cyclopentylpropanamide

A mixture of (R)-tert-butyl3-cyano-1-(cyclopentylamino)-1-oxopropan-2-ylcarbamate and 50% TFA/DCM(10 mL) was stirred for 1 h. Following reaction, the mixture wasconcentrated to afford the title compound as a clear oil (TFA salt,0.265 g, 41%). The product was pure by TLC (visualized by ninhydrinstain).

PREPARATION K:5-chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

STEP A: 5-chloro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde

To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (5.0g, 27.7 mmol) in EtOH (100 mL) was added iodine (8.43 g, 33.2 mmol),sodium iodide (4.98 g, 33.2 mmol), and aqueous NaOH (1N, 35 mL, 35mmol). After stirring for 4 h at room temperature, the reaction mixturewas diluted with water (200 mL). An orange precipitate was collected byfiltration and dried under vacuum. The solid was dissolved in DMF (60mL) and sodium hydride (60%, 1.33 g, 33.2 mmol) was slowly added. Thedeep red solution was stirred for 30 min at room temperature. Tosylchloride (5.81 g, 30.5 mmol) was added and the mixture was stirred atroom temperature for 2 h. The mixture was diluted with EtOAc and thereaction was quenched with water. The organics were separated, washedwith aqueous NaHSO₃ (0.1 N) and brine, dried over MgSO₄, andconcentrated. Purification by silica gel chromatography (3:1:1hexane/DCM/EtOAc) gave the title compound as a yellow solid (8.96 g,70%). ¹H NMR (500 MHz, DMSO-d₆) δ 3.15 (s, 3H), 8.24 (d, J=8.5 Hz, 2H),8.81 (d, J=8.5 Hz, 2H), 9.17 (s, 1H), 9.38 (s, 1H), 11.81 (s, 1H). [M+H]calc'd for C₁₅H₁₀ClIN₂O₃S, 461, 463; found, 461, 463.

STEP B: 5-chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

Lithium chloride (1.05 g, 24.7 mmol) and lithium formate monohydrate(1.73 g, 24.7 mmol) were combined in a dry sealable tube under nitrogen.DMF (20 mL),5-chloro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (3.8 g,8.25 mmol), acetic anhydride (1.56 mL, 16.5 mmol) and palladium acetate(185 mg, 0.83 mmol) were added. DIPEA (2.87 mL) was added, and thereaction tube was sealed and heated at 52° C. for 3 h. The reactionmixture was taken up in MeOH/DCM (20%) and filtered to remove theinsoluble black carbon material. The yellow solution was concentrated invacuo, dissolved in MeOH/DCM (10%), and washed with aqueous HCl (0.1N).The aqueous layer was extracted with MeOH/DCM (10%, 2×). The organicswere combined, dried over MgSO₄, and concentrated in vacuo. Purificationby silica gel chromatography (10-15% MeOH/DCM) gave the title compoundas a light tan solid (2.34 g, 75%). ¹H NMR (500 MHz, CD₃OD) δ 3.15 (s,3H), 8.24 (d, J=8.5 Hz, 2H), 8.81 (d, J=8.5 Hz, 2H), 9.17 (s, 1H), 9.38(s, 1H), 11.81 (s, 1H). [M+H] calc'd for C₁₆H₁₁ClN₂O₅S, 379, 381; found,379, 381.

Example 30(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamide

STEP A:(R)-5-chloro-4-((3-cyano-1-(cyclopentylamino)-1-oxopropan-2-ylamino)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

A mixture of sodium triacetoxyborohydride (26.5 mg, 0.125 mmol) and(R)-2-amino-3-cyano-N-cyclopentylpropanamide (22.70 mg, 0.125 mmol) inDCM (1 mL) was stirred at room temperature for 10 min. The reactionmixture was cooled to 0° C. A solution of5-chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid(30 mg, 0.063 mmol) in DCM (1 mL) was added. The reaction mixture wasstirred at 0° C. for 20 min and then concentrated to afford the titlecompound. [M+H] calc'd for C₂₆H₂₈ClN₅O₅S, 544; found, 544.2.

STEP B:(R)-2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamide

A mixture of(R)-5-chloro-4-((3-cyano-1-(cyclopentylamino)-1-oxopropan-2-ylamino)methyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid, THF (5 mL), HATU (28.6 mg, 0.075 mmol) and 4-methylmorpholine(19.01 mg, 0.188 mmol) was stirred at room temperature for 2 h. Theproduct was purified via preparative mass trigger LC-MS (AcCN/H₂O,5-90%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound. [M+H] calc'd for C₂₅H₂₄ClN₅O₄S, 526;found, 526.2.

STEP C:(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamide

To a solution of(R)-2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamidein MeOH (2 mL) was added aqueous NaOH (1N, 0.5 mL). The reaction mixturewas stirred for 20 min and the product was purified via preparative masstrigger LC-MS (AcCN/H₂O, 5-50%). The fractions were collected,concentrated, and dried in vacuo to afford the title compound as ayellow oil (0.5 mg, 2.1% from Step A starting material). ¹H NMR (400MHz, CD₃OD) δ 1.37-1.72 (m, 4H) 1.83-1.95 (m, 4H) 3.22-3.26 (m, 2H)3.69-3.76 (m, 1H) 5.11 (s, 1H) 5.14-5.17 (m, 1H) 5.18 (s, 1H) 7.88 (s,1H) 8.27 (s, 1H). [M+H] calc'd for C₁₈H₁₈ClN₅O₂, 372; found, 372.4.

Example 31N-cyclopentyl-1-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)cyclopentanecarboxamide

STEP A:1-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)cyclopentanecarboxylicacid

To a 10 mL round bottom flask was added sodium triacetoxyborohydride(104 mg, 0.493 mmol) and 1-aminocyclopentanecarboxylic acid (42.4 mg,0.329 mmol) in DCM (2 mL). The reaction mixture was stirred at roomtemperature for 30 min after which was added 1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (50 mg, 0.164 mmol)in DCM (2 mL). The reaction was stirred at room temperature for 2 h andthen quenched with MeOH (3 drops). The mixture was concentrated toafford the title compound, which was used in the next step withoutfurther purification. [M+H] calc'd for C₂₁H₂₇N₃O₆, 418; found, 418.3.

STEP B: 1-tert-butyl 3-methyl4-((1-(cyclopentylcarbamoyl)cyclopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

To1-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)cyclopentanecarboxylicacid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine(70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). Thesuspension was stirred at 43° C. for 36 h to afford the title compound,which was used in the next step without further purification. [M+H]calc'd for C₂₆H₃₆N₄O₅, 485; found, 485.4.

STEP C:4-((1-(cyclopentylcarbamoyl)cyclopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

Crude 1-tert-butyl 3-methyl4-((1-(cyclopentylcarbamoyl)cyclopentylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylatewas concentrated and re-dissolved in MeOH (1 mL). Aqueous NaOH (12N, 2mL) was added and the reaction mixture was stirred at 53° C. for 16 h.The product was purified via preparative mass trigger LC-MS (AcCN/H₂O,5-50%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound. [M+H] calc'd for C₂₀H₂₆N₄O₃, 371; found,371.6.

STEP D:N-cyclopentyl-1-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)cyclopentanecarboxamide

In a manner similar to Step C of Example 19,4-(1-(cyclopentylcarbamoyl)cyclo-pentylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was cyclized in a mixture of THF (2 mL), HATU (94 mg, 0.246 mmol)and 4-methylmorpholine (83 mg, 0.822 mmol) and the product was purifiedvia preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow oil (2.7 mg, 4.8% from Step A starting material). ¹H NMR(500 MHz, CD₃OD) δ 1.45 (d, J=7.32 Hz, 1H) 1.52 (d, J=4.88 Hz, 1H) 1.61(br. s., 1H) 1.79 (br. s., 2H) 1.82-1.91 (m, 1H) 1.96-2.02 (m, 1H)2.06-2.23 (m, 4H) 2.50 (d, J=13.18 Hz, 1H) 2.98 (br. s., 1H) 3.21-3.29(m, 2H) 3.38-3.42 (m, 1H) 4.03-4.17 (m, 1H) 5.29 (s, 1H) 7.20 (br. s.,1H) 7.75 (s, 1H) 8.31 (br. s., 1H). [M+H] calc'd for C₂₀H₂₄N₄O₂, 353;found, 353.5.

PREPARATION L:(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid

STEP A: (R)-tert-butyl2-((5-chloro-3-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3-methylbutanoate

Sodium triacetoxyborohydride (517 mg, 2.44 mmol) and D-valine-tert-butylester, HCl salt (512 mg, 2.44 mmol) were combined in DCM (15 mL). Thereaction mixture was stirred at room temperature for 20 min and wascooled to 0° C.5-Chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid(660 mg, 1.74 mmol) was added and the reaction was stirred at 0° C. for1 h. The solution was concentrated in vacuo to give the title compoundas a yellow foam, which was used in the next step without furtherpurification.

STEP B: (R)-tert-butyl2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate

(R)-tert-butyl2-((5-chloro-3-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3-methylbutanoatewas re-dissolved in THF (40 mL). HATU (994 mg, 2.61 mmol) andN-methylmorpholine (291 μL, 2.61 mmol) were added and the reactionmixture was stirred at 50° C. for 2 h. Additional HATU (497 mg, 1.30mmol) and N-methylmorpholine (85 μL, 1.30 mmol) were added and thereaction mixture was stirred for an additional 2 h at 50° C. Thereaction mixture was subsequently cooled, diluted with EtOAc, and washedwith brine. The organics were dried over MgSO₄ and concentrated invacuo. Purification by silica gel chromatography (1:2:2EtOAc/Hexanes/DCM) gave the title compound as a yellow solid (660 mg,73% from Step A starting material). ¹H NMR (500 MHz, CDCl₃) δ 0.80 (d,J=7.0 Hz, 3H), 1.01 (d, J=7.0 Hz, 3H), 1.36 (s, 9H), 2.29-2.36 (m, 1H),2.34 (s, 3H), 4.77-5.04 (m, 3H), 7.44 (d, J=8.5 Hz, 2H), 8.06 (d, J=8.5Hz, 2H), 8.28 (s, 1H), 8.47 (s, 1H). [M+H] calc'd for C₂₅H₂₈ClN₃O₅S,518, 520; found, 518, 520.

STEP C:(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid

A mixture of (R)-tert-butyl2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate(650 mg, 1.25 mmol), EtOH (4 mL), and aqueous NaOH (1N, 2 mL) wasstirred at room temperature for 40 min. The mixture was subsequentlydiluted with DCM and washed with brine. The organics were dried overMgSO₄ and concentrated in vacuo. Purification by silica gelchromatography (5% MeOH/DCM) gave a yellow oil (425 mg), which wasdissolved in 50% TFA/DCM. The solution was stirred at room temperaturefor 1 h, concentrated, and dried under vacuum to give the title compoundas a yellow solid (360 mg, 93%). ¹H NMR (500 MHz, CD₃OD) δ 0.91 (d,J=7.0 Hz, 3H), 1.11 (d, J=7.0 Hz, 3H), 2.36-2.47 (m, 1H), 4.80-5.08 (m,3H), 7.76 (s, 1H), 8.19 (s, 1H). [M+H] calc'd for C₁₄H₁₄ClN₃O₃, 308,310; found, 308, 310.

Example 32(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(cyanomethyl)-3-methylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol). THF (0.5 mL), 2-aminoacetonitrile (3.64 mg,0.065 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solutionwas stirred at 25° C. for 1 h. The reaction mixture was purified viapreparative mass trigger LC-MS (AcCN/H₂O, 5-50%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow oil (3.8 mg, 33.8%). ¹H NMR (400 MHz, CD₃OD) δ 0.85-0.97 (m,3H) 1.02 (d, J=6.57 Hz, 1H) 1.07 (d, J=6.32 Hz, 2H) 2.53 (dt, J=11.18,6.54 Hz, 1H) 3.52-3.86 (m, 2H) 4.89-5.04 (m, 1H) 5.07 (d, J=11.37 Hz,1H) 5.51 (d, J=10.86 Hz, 1H) 7.80-7.89 (m, 1H) 8.13-8.34 (m, 1H). [M+H]calc'd for C₁₆H₁₆ClN₅O₂, 346; found, 346.4.

Example 331-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-3-carbonitrile

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol). THF (0.5 mL), pyrrolidine-3-carbonitrile (3.12mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and thesolution was stirred at 25° C. for 1 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (1.3 mg, 10.4%). ¹H NMR (400 MHz, CD₃OD)δ 0.92 (s, 3H) 1.00-1.12 (m, 3H) 2.27-2.35 (m, 1H) 2.56 (d, J=6.57 Hz,1H) 3.40 (d, J=6.82 Hz, 1H) 3.51-3.68 (m, 1H) 3.74 (d, J=6.57 Hz, 1H)3.79-3.94 (m, 1H) 3.96-4.03 (m, 1H) 4.88-5.00 (m, 2H) 5.03-5.23 (m, 1H)5.39-5.48 (m, 1H) 7.87 (d, J=12.63 Hz, 1H) 8.21-8.30 (m, 1H). [M+H]calc'd for C₁₉H₂₀ClN₅O₂, 386; found, 386.4.

Example 34(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)piperidine-4-carbonitrile

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol). THF (0.5 mL), piperidine-4-carbonitrile (3.58mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and thesolution was stirred at 25° C. for 1 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (3.3 mg, 25.4%). ¹H NMR (400 MHz, CD₃OD)δ 0.84-0.93 (m, 3H) 0.96-1.08 (m, 3H) 1.42-1.60 (m, 1H) 1.72-1.82 (m,2H) 1.82-2.00 (m, 1H) 2.49-2.66 (m, 1H) 2.92-3.07 (m, 1H) 3.49-3.73 (m,2H) 3.78-4.00 (m, 1H) 4.00-4.11 (m, 1H) 4.90 (d, J=7.58 Hz, 1H)4.92-5.01 (m, 1H) 5.53 (dd, J=10.86, 3.54 Hz, 1H) 7.82-7.92 (m, 1H)8.15-8.30 (m, 1H). [M+H] calc'd for C₂₀H₂₂ClN₅O₂, 400; found, 400.4.

Example 35(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(4-cyanophenyl)-3-methylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol). THF (0.5 mL), 4-aminobenzonitrile (7.68 mg,0.065 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solutionwas stirred at 25° C. for 1 h. The reaction mixture was purified viapreparative mass trigger LC-MS (AcCN/H₂O, 5-50%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow oil (2 mg, 15.1%). ¹H NMR (400 MHz, CD₃OD) δ 0.90-1.03 (m,3H) 1.07-1.15 (m, 3H) 2.59 (dt, J=11.24, 6.63 Hz, 1H) 5.01 (d, J=19.45Hz, 1H) 5.21 (d, J=11.12 Hz, 1H) 5.42 (d, J=19.45 Hz, 1H) 7.64-7.66 (m,1H) 7.66-7.68 (m, 1H) 7.80-7.82 (m, 1H) 7.82-7.84 (m, 1H) 7.86 (s, 1H)8.25 (s, 1H). [M+H] calc'd for C₂₁H₁₈ClN₅O₂, 408; found, 408.4.

Example 36(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(3-cyanophenyl)-3-methylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol). THF (0.5 mL), 3-aminobenzonitrile (7.68 mg,0.065 mmol) and HATU (14.83 mg, 0.039 mmol) were added and the solutionwas stirred at 25° C. for 1 h. The reaction mixture was purified viapreparative mass trigger LC-MS (AcCN/H₂O, 5-50%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow oil (1.8 mg, 13.58%). ¹H NMR (400 MHz, CD₃OD) δ 1.00 (d,J=6.60 Hz, 3H) 1.12 (d, J=6.57 Hz, 3H) 2.60 (s, 1H) 5.02 (d, J=19.71 Hz,1H) 5.20 (d, J=11.12 Hz, 1H) 5.43 (d, J=19.71 Hz, 1H) 7.43 (dt, J=7.77,1.42 Hz, 1H) 7.48 (t, J=7.96 Hz, 1H) 7.81-7.85 (m, 1H) 7.86 (s, 1H) 8.08(t, J=1.64 Hz, 1H) 8.25 (s, 1H). [M+H] calc'd for C₂₁H₁₈ClN₅O₂, 408;found, 408.4.

Example 37(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N—((S)-1-cyanobutan-2-yl)-3-methylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol). THF (0.5 mL), (S)-3-aminopentanenitrile (3.19mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and thesolution was stirred at 25° C. for 1 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (3.1 mg, 24.6%). ¹H NMR (400 MHz, CD₃OD)δ 0.93 (d, J=6.57 Hz, 3H) 0.97 (t, J=7.33 Hz, 3H) 1.07 (d, J=6.57 Hz,3H) 1.51-1.69 (m, 2H) 2.44-2.58 (m, 2H) 2.58-2.72 (m, 1H) 4.07 (br. s.,1H) 4.86-4.97 (m, 1H) 5.08 (d, J=11.12 Hz, 1H) 5.31 (d, J=19.71 Hz, 1H)7.84 (s, 1H) 8.23 (s, 1H). [M+H] calc'd for C₁₉H₂₂ClN₅O₂, 388; found,388.4.

Example 38(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N—((R)-1-cyanobutan-2-yl)-3-methylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol). THF (0.5 mL), (R)-3-aminopentanenitrile (3.19mg, 0.032 mmol) and HATU (14.83 mg, 0.039 mmol) were added and thesolution was stirred at 25° C. for 1 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 5-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (2.9 mg, 23.01%). ¹H NMR (400 MHz, CD₃OD)δ 0.82 (t, J=7.45 Hz, 3H) 0.89-0.99 (m, 3H) 1.11 (d, J=6.57 Hz, 3H)1.44-1.68 (m, 2H) 2.41-2.56 (m, 1H) 2.63 (dd, J=16.93, 7.33 Hz, 1H) 2.76(dd, J=16.93, 5.05 Hz, 1H) 3.99 (d, J=10.61 Hz, 1H) 4.95 (d, J=19.96 Hz,1H) 5.05 (d, J=11.37 Hz, 1H) 5.35 (d, J=19.71 Hz, 1H) 7.85 (s, 1H)8.20-8.27 (m, 1H). [M+H] calc'd for C₁₉H₂₂ClN₅O₂, 388; found, 388.4.

Example 39(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol). THF (0.5 mL), azetidine-3-carbonitrile (2.7mg, 0.032 mmol), 4-methylmorpholine (4.93 mg, 0.049 mmol) and HATU(14.83 mg, 0.039 mmol) were added and the solution was stirred at 25° C.for 1 h. The reaction mixture was purified via preparative mass triggerLC-MS (AcCN/H₂O, 5-50%). The fractions were collected, concentrated, anddried in vacuo to afford the title compound as a semi-solid (3.7 mg,30.6%). ¹H NMR (400 MHz, CD₃OD) δ 0.94 (t, J=6.32 Hz, 3H) 1.07 (dd,J=18.19, 6.32 Hz, 3H) 2.44-2.59 (m, 1H) 3.47-3.79 (m, 1H) 4.15-4.40 (m,2H) 4.57 (dt, J=9.73, 4.99 Hz, 1H) 4.63-4.78 (m, 1H) 4.84 (d, J=19.71Hz, 1H) 5.06-5.30 (m, 2H) 7.82 (d, J=11.37 Hz, 1H) 8.25 (d, J=5.56 Hz,1H). [M+H] calc'd for C₁₈H₁₈ClN₅O₂, 372; found, 372.4.

PREPARATION M:(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoicacid

STEP A:(R)-4-((1-(benzyloxy)-3,3-dimethyl-1-oxobutan-2-ylamino)methyl)-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

To a 10 mL round bottom flask was added sodium triacetoxyborohydride (86mg, 0.407 mmol), (R)-benzyl 2-amino-3,3-dimethylbutanoate (130 mg, 0.407mmol) and DCM (2 mL). The mixture was stirred at room temperature for 10min and then cooled to 0° C.5-Chloro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid(130 mg, 0.271 mmol) was added and the reaction mixture was stirred at0° C. for 20 min to afford the title compound. [M+H] calc'd forC₂₉H₃₀ClN₃O₆S, 584; found, 584.0.

STEP B: (R)-benzyl2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate

Crude(R)-4-((1-(benzyloxy)-3,3-dimethyl-1-oxobutan-2-ylamino)methyl)-5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was heated in HATU (124 mg, 0.326 mmol) and 4-methylmorpholine (82mg, 0.814 mmol) at reflux for 3 h. The reaction mixture was subsequentlyconcentrated and dried in vacuo to afford the title compound. [M+H]calc'd for C₂₉H₂₈ClN₃O₅S, 566; found, 566.0.

STEP C:(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoicacid

Crude (R)-benzyl2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoatewas dissolved in MeOH/THF (50%, 5 mL). Aqueous NaOH (1N, 2 mL) wasadded. The reaction mixture was stirred at 50° C. for 16 h and waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 20-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (34 mg, 38.9% from Step A startingmaterial). ¹H NMR (400 MHz, CD₃OD) δ 1.22-1.32 (m, 9H) 4.92 (br. s., 1H)5.18 (d, J=18.95 Hz, 1H) 5.33 (d, J=18.95 Hz, 1H) 7.88 (s, 1H) 8.29 (s,1H). [M+H] calc'd for C₁₅H₁₆ClN₃O₃, 322; found, 322.5.

Example 40(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(2-cyanoethyl)-3,3-dimethylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoicacid (5 mg, 0.016 mmol). DMF (0.5 mL), 3-aminopropanenitrile (1.089 mg,0.016 mmol), HOBt (3.57 mg, 0.023 mmol), EDC (4.47 mg, 0.023 mmol) andN,N-dimethylpyridin-4-amine (1.898 mg, 0.016 mmol) were added and thesolution was stirred at 25° C. for 4 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 20-50%). Thefractions were collected, concentrated, and dried in vacuo to afford thetitle compound as a yellow oil (3.2 mg, 55.1%). ¹H NMR (500 MHz, CD₃OD)δ 1.19 (s, 9H) 2.63-2.72 (m, 2H) 3.38-3.53 (m, 2H) 4.89 (br. s., 1H)5.29 (d, J=19.04 Hz, 1H) 5.41 (d, J=19.00 Hz, 2H) 7.85 (s, 1H) 8.24 (s,1H) 8.55 (d, J=4.88 Hz, 1H). [M+H] calc'd for C₁₈H₂₀ClN₅O₂, 374; found,374.5.

Example 41(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoyl)azetidine-3-carbonitrile

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoicacid (25 mg, 0.078 mmol) under nitrogen. THF (0.5 mL),azetidine-3-carbonitrile hydrochloride (18.45 mg, 0.155 mmol), HATU and4-methylmorpholine (11.79 mg, 0.117 mmol) were added and the solutionwas stirred at 25° C. for 1 h. The reaction mixture was purified viapreparative mass trigger LC-MS (AcCN/H₂O, 15-40%). The fractions werecollected, concentrated, and dried in vacuo to afford the title compoundas a yellow semi-solid (4.1 mg, 13.7%). ¹H NMR (400 MHz, CD₃OD) δ 1.17(s, 9H) 3.50-3.78 (m, 1H) 4.17 (br. s., 1H) 4.25-4.37 (m, 1H) 4.41-4.69(m, 2H) 5.17-5.30 (m, 2H) 5.44 (s, 1H) 7.87 (br. s., 1H) 8.25 (s, 1H).[M+H] calc'd for C₁₉H₂₀ClN₅O₂, 386; found, 386.4.

PREPARATION N:5-fluoro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

STEP A: (5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol

To an oven-dried 200 mL round bottom flask equipped for stirring wasadded methyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (2.4 g,12.36 mmol) under nitrogen. THF (100 mL) was added and the colorlesssolution was cooled to 0° C. Lithium aluminum hydride (27.2 mL, 27.2mmol) was added and the solution was stirred at 0° C. for 3 h. Thereaction was quenched with EtOAc (100 mL); brine (100 mL) was added, andthe aqueous phase was extracted three times with EtOAc. The organicswere dried over Na₂SO₄ and concentrated to afford the title compound asa yellow fine powder (2.01 g, 98%). ¹H NMR (400 MHz, CD₃OD) δ 4.96 (d,J=1.26 Hz, 2H) 6.72 (d, J=3.54 Hz, 1H) 7.44 (d, J=3.54 Hz, 1H) 8.06 (d,J=2.78 Hz, 1H). [M+H] calc'd for C₈H₇FN₂O, 167; found, 167.5.

STEP B: 5-fluoro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde

To a 250 mL round bottom flask equipped with a stirring bar was added(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (2.01 g, 12.10 mmol) inTHF (100 mL) under nitrogen. Manganese dioxide (10.52 g, 121 mmol) wasadded and the reaction mixture was stirred at 60° C. for 2 h. Theorganics were filtered through a pad of Celite, rinsed with EtOAc (100mL) and concentrated. The resulting solid was triturated with EtOAc (50mL) and filtered to give the title compound as a light yellow solid (1.3g, 65.5%). ¹H NMR (400 MHz, CD₃OD) δ 4.59 (s, 1H) 5.34 (d, J=3.54 Hz,1H) 5.86-6.08 (m, 1H) 6.58 (d, J=3.28 Hz, 1H). [M+H] calc'd forC₈H₅FN₂O, 165; found, 165.5.

STEP C: 5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde

To a solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (2.45g, 14.93 mmol) in EtOH (20 mL) was added iodine (4.55 g, 17.91 mmol),sodium iodide (2.68 g, 17.91 mmol) and aqueous NaOH (1N, 15 mL). Thereaction mixture was stirred for 4 h at 25° C. and diluted with aqueousNaHSO₃ (0.1N). An orange precipitate was collected by filtration anddried under vacuum to afford the title compound as a yellow solid (6.54g, 82%). [M+H] calc'd for C₈H₄F_(I)N₂O, 291; found, 291.5.

STEP D: 5-fluoro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde

To a solution of5-fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde in DMF (12 mL)was added NaOH (0.716 g, 17.91 mmol). The deep red solution was stirredfor 30 min after which 4-methylbenzene-1-sulfonyl chloride (3.13 g,16.42 mmol) was added. The reaction mixture was stirred for 2 h,subsequently diluted with EtOAc, and washed with water and brine. Theextracts were dried over MgSO₄ and concentrated. Purification by silicacolumn chromatography (DCM, 100%) afforded the title compound as lightyellow solid (3.65 g, 55%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.36 (s, 3H)7.45 (m, J=8.08 Hz, 2H) 8.02 (m, J=8.34 Hz, 2H) 8.42 (s, 1H) 8.59 (d,J=2.53 Hz, 1H) 11.13 (s, 1H). [M+H] calc'd for C₁₅H₁₀FIN₂O₃S, 445;found, 445.1.

STEP E: 5-fluoro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

Lithium chloride (0.472 g, 11.14 mmol) and lithium formate (0.579 g,11.14 mmol) were combined in a sealable dried tube. DMF (10 mL),5-fluoro-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (1.650g, 3.71 mmol), acetic anhydride (0.702 mL, 7.43 mmol) anddiacetoxypalladium (0.083 g, 0.371 mmol) were added.N-Ethyl-N-isopropylpropan-2-amine (1.294 mL, 7.43 mmol) was added andthe mixture was sealed and heated at 56° C. for 3 h. The reactionmixture was taken up in MeOH/DCM (20%) and filtered. The yellow solutionwas concentrated and the residue was dissolved in MeOH/DCM (10%) andwashed with aqueous HCl (0.1N). The aqueous phase was extracted two moretimes. The organics were combined, dried over MgSO₄ and concentrated toan orange oil, which was triturated in ether (300 mL). The precipitatewas filtered and dried in vacuo to afford the title compound as lightyellow solid (1.15 g, 77%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.37 (s, 3H)7.47 (d, J=8.08 Hz, 2H) 8.10 (d, J=8.10 Hz, 2H) 8.54-8.65 (m, 2H) 10.60(s, 1H) 13.45 (br. s., 1H). [M+H] calc'd for C₁₅H₁₀FIN₂O₃S, 363; found,363.4.

PREPARATION O:(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid

STEP A:(R)-4-((1-tert-butoxy-3-methyl-1-oxobutan-2-ylamino)methyl)-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

A mixture of sodium triacetoxyborohydride (1.143 g, 5.39 mmol),(R)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (1.131 g, 5.39mmol) and DCM (20 mL) was stirred at room temperature for 10 min. Thereaction mixture was cooled to 0° C.5-fluoro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.299g, 3.60 mmol) was added and the reaction was stirred at 0° C. for 20 minto afford the title compound. [M+H] calc'd for C₂₅H₃₀FN₃O₆S, 520; found,520.2.

STEP B: (R)-tert-butyl2-(6-fluoro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate

Crude(R)-4-((1-tert-butoxy-3-methyl-1-oxobutan-2-ylamino)methyl)-5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid was heated in HATU (2.60 g, 7.19 mmol) and 4-methylmorpholine(1.091 g, 10.79 mmol) at reflux for 3 h. The reaction was incomplete byLC-MS. HATU (1.37 g, mmol, 3.79 mmol) and 4-methylmorpholine (1.091 g,10.79 mmol) were added and the reaction mixture was stirred at refluxfor 16 h. Following reaction, the mixture was washed with aqueous NaHCO₃(sat.) and extracted with DCM. The organics were washed with brine,dried over Na₂SO₄, and concentrated to a brown oil. Purification bysilica column chromatography (EtOAc/DCM, 0-20%) afforded the titlecompound as a white foam. (0.933 g, 51.7%). ¹H NMR (400 MHz, DMSO-d₆) δ0.80 (d, J=6.57 Hz, 3H) 1.02 (d, J=6.57 Hz, 3H) 1.39 (s, 9H) 2.31-2.39(m, 4H) 4.77 (d, J=10.61 Hz, 1H) 5.02 (d, J=7.58 Hz, 2H) 7.46 (d, J=7.83Hz, 2H) 8.08 (d, J=8.34 Hz, 2H) 8.29 (s, 1H) 8.44 (d, J=2.78 Hz, 1H).[M+H] calc'd for C₂₅H₂₈FN₃O₅S, 502; found, 502.3.

STEP C: (R)-tert-butyl2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate

To a stirred solution of (R)-tert-butyl2-(6-fluoro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate(933 mg, 1.860 mmol) in MeOH (4 mL) was added aqueous NaOH (1N, 2 mL).The reaction mixture was stirred at 25° C. for 40 min. The reaction waspartitioned between DCM and brine. The organics were dried over MgSO₄and concentrated. Purification by silica column chromatography(MeOH/DCM, 0-5%) afforded the title compound as a yellow oil (0.39 g,60.4%). [M+H] calc'd for C₁₈H₂₂FN₃O₃, 348; found, 348.5.

STEP D:(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid

(R)-tert-Butyl2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoatewas stirred in DCM/TFA (50%, 10 mL) for 1 h, concentrated and dried invacuo to afford the title compound as a beige solid (0.32 g, 59.1%). ¹HNMR (400 MHz, DMSO-d₆) δ 0.84 (d, J=6.30 Hz, 3H) 1.04 (d, J=6.32 Hz, 3H)2.39 (dt, J=10.61, 6.57 Hz, 1H) 4.83 (d, J=10.61 Hz, 1H) 5.04 (d, J=9.60Hz, 2H) 7.98 (s, 1H) 8.26 (s, 1H) 12.39 (br. s., 1H). [M+H] calc'd forC₁₄H₁₄FN₃O₃, 292; found, 292.5.

Example 42(R)-1-(2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (60 mg, 0.206 mmol). DMF (0.5 mL), azetidine-3-carbonitrilehydrochloride (0.309, 36.6 mg), HOBt (47.3 mg, 0.309 mmol), EDC (59.2mg, 0.309 mmol) and N,N-dimethylpyridin-4-amine (37.7 mg, 0.309 mmol)were added and the solution was stirred at 25° C. for 4 h. The reactionmixture was purified via preparative mass trigger LC-MS (AcCN/H₂O,20-50%). The fractions were collected, concentrated, and dried in vacuoto afford the title compound as a TFA salt. The residue was furtherpurified using silica column chromatography (MeOH/DCM, 0-10%) which gavethe title compound as a white solid (free base, 25.2 mg, 34.4%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.78 (dd, J=6.57, 3.79 Hz, 3H) 0.95 (dd, J=13.01,6.44 Hz, 3H) 1.09 (t, J=6.95 Hz, 1H) 3.53-3.86 (m, 1H) 3.94-4.10 (m, 1H)4.10-4.29 (m, 2H) 4.29-4.48 (m, 1H) 4.87 (dd, J=18.82, 8.21 Hz, 1H)4.96-5.14 (m, 2H) 7.99 (dd, J=5.43, 2.40 Hz, 1H) 8.25 (t, J=2.78 Hz, 1H)12.39 (br. s., 1H). [M+H] calc'd for C₁₈H₁₈FN₅O₂, 356; found, 356.5.

Example 43(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol). DMF (0.5 mL), 3-(methylamino)propanenitrile(0.077, 6.5 mg), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol)and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and thesolution was stirred at 25° C. for 4 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 20-50%). Thefractions were collected and lyophilized to afford the title compound asa yellow oil (6.1 mg, 33.1%). ¹H NMR (400 MHz, CD₃OD) δ 0.79-0.93 (m,3H) 0.97-1.06 (m, 3H) 2.49-2.67 (m, 1H) 2.71-2.80 (m, 2H) 3.00 (s, 1H)3.24 (s, 2H) 3.57-4.02 (m, 2H) 4.99 (s, 1H) 5.08-5.22 (m, 1H) 5.52-5.63(m, 1H) 7.80-7.96 (m, 1H) 8.16 (d, J=3.03 Hz, 1H). [M+H] calc'd forC₁₈H₂₀FN₅O₂, 358; found, 358.4.

Example 44(2R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(tetrahydrofuran-3-yl)butanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol). DMF (0.5 mL), tetrahydrofuran-3-amine (0.077,6.7 mg), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) andN,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and thesolution was stirred at 25° C. for 4 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 20-50%). Thefractions were collected and lyophilized to afford the title compound asa white solid (7.3 mg, 39.3%). ¹H NMR (400 MHz, CD₃OD) δ 0.93 (d, J=6.57Hz, 3H) 1.04 (dd, J=6.57, 2.78 Hz, 3H) 1.74-1.95 (m, 1H) 2.21 (d, J=7.83Hz, 1H) 2.42-2.54 (m, 1H) 3.50-3.67 (m, 1H) 3.69-3.97 (m, 3H) 4.37 (td,J=3.85, 1.89 Hz, 1H) 4.96-5.12 (m, 2H) 5.36-5.52 (m, 1H) 7.86 (s, 1H)8.17 (d, J=3.28 Hz, 1H). [M+H] calc'd for C₁₈H₂₁FN₄O₃, 361; found,361.4.

Example 45(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(1,1-dioxidotetrahydrothien-3-yl)butanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol). DMF (0.5 mL),1,1-dioxidotetrahydrothien-3-ylamine (10.4 mg, 0.077), HOBt (11.83 mg,0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine(9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C.for 4 h. The reaction mixture was purified via preparative mass triggerLC-MS (AcCN/H₂O, 20-50%). The fractions were collected and lyophilizedto afford the title compound as a white solid (5.1 mg, 24.3%). ¹H NMR(400 MHz, CD₃OD) δ 0.93 (dd, J=6.57, 1.26 Hz, 3H) 1.05 (dd, J=6.32, 3.79Hz, 3H) 2.06-2.28 (m, 1H) 2.40-2.59 (m, 2H) 2.98 (td, J=12.57, 7.45 Hz,1H) 3.04-3.18 (m, 1H) 3.21-3.29 (m, 1H) 3.35-3.53 (m, 1H) 4.51-4.66 (m,1H) 4.95-5.12 (m, 2H) 5.40 (dd, J=19.20, 13.39 Hz, 1H) 7.83-7.89 (m, 1H)8.17 (dd, J=3.28, 1.52 Hz, 1H). [M+H] calc'd for C₁₈H₂₁FN₄O₄S, 409;found, 409.3.

Example 46(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(2-(methylsulfonyl)ethyl)butanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol) under nitrogen. DMF (0.5 mL),2-(methylsulfonyl)ethanamine hydrochloride (8.2 mg, 0.051 mmol), HOBt(11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) andN,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and thesolution was stirred at 25° C. for 4 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 20-50%). Thefractions were collected and lyophilized to afford the title compound asa white solid (8 mg, 39.2%). ¹H NMR (400 MHz, CD₃OD) δ 0.91 (d, J=6.82Hz, 3H) 1.05 (d, J=6.32 Hz, 3H) 2.50 (dq, J=17.94, 6.57 Hz, 1H) 2.92 (s,3H) 3.22-3.28 (m, 1H) 3.33-3.38 (m, 1H) 3.61 (dt, J=14.40, 6.57 Hz, 1H)3.73 (dt, J=14.40, 6.57 Hz, 1H) 4.94-5.13 (m, 2H) 5.19-5.40 (m, 1H) 7.85(s, 1H) 8.17 (d, J=3.28 Hz, 1H). [M+H] calc'd for C₁₇H₂₁FN₄O₄S, 398;found, 398.3.

PREPARATION P: (1,1-dioxo-hexahydro-6-thiopyran-4-yl)-aminehydrochloride

To a 100 mL round bottom flask equipped for stirring was addedbenzyl-(1,1-dioxo-hexahydro-6-thiopyran-4-yl)-amine (500 mg, 2.089 mmol)and palladium on carbon (111 mg, 1.045 mmol) under nitrogen. Methanol(15 mL) and aqueous HCl (4N, 0.172 mL, 2.089 mmol) were added and thesolution was stirred at 60° C. for 48 h. The reaction mixture wasfiltered through Celite and concentrated to afford the title compound asan orange solid (241 mg, 62.1%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.88-2.12(m, 2H) 2.26 (d, J=11.87 Hz, 2H) 3.08-3.22 (m, 2H) 3.23-3.29 (m, 2H)3.39 (br. s., 1H) 8.34 (br. s., 2H).

Example 47(R)—N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol) under nitrogen. DMF (0.5 mL),(1,1-dioxo-hexahydro-6-thiopyran-4-yl)-amine hydrochloride (10 mg, 0.051mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) andN,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and thesolution was stirred at 25° C. for 4 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 20-50%). Thefractions were collected and lyophilized to afford the title compound asa yellow oil (6.4 mg, 29.4%). ¹H NMR (500 MHz, CD₃OD) δ 0.93 (d, J=6.83Hz, 3H) 1.04 (dd, J=6.35, 2.93 Hz, 3H) 1.61-1.80 (m, 1H) 1.89-2.01 (m,1H) 2.06-2.30 (m, 4H) 2.36-2.54 (m, 2H) 3.32-3.38 (m, 1H) 4.19-4.38 (m,1H) 4.93-5.11 (m, 2H) 5.45 (dd, J=18.79, 5.13 Hz, 1H) 7.86 (s, 1H) 8.17(d, J=2.93 Hz, 1H). [M+H] calc'd for C₁₉H₂₃FN₄O₄S, 423; found, 423.3.

Example 484-{(1R)-1-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-2-methylpropyl}-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol). DMF (0.5 mL), thiomorpholine 1,1-dioxidehydrochloride (8.84 mg, 0.51 mmol), HOBt (11.83 mg, 0.077 mmol), EDC(14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077mmol) were added and the solution was stirred at 25° C. for 4 h. Thereaction mixture was purified via preparative mass trigger LC-MS(AcCN/H₂O, 20-50%). The fractions were collected and lyophilized toafford the title compound as a white solid (9.8 mg, 46.6%). ¹H NMR (400MHz, CD₃OD) δ 0.92 (d, J=6.82 Hz, 3H) 1.02 (d, J=6.32 Hz, 3H) 2.60 (dt,J=10.61, 6.57 Hz, 1H) 2.90-3.03 (m, 1H) 3.03-3.25 (m, 3H) 3.86-4.01 (m,1H) 4.13 (ddd, J=14.78, 8.59, 2.40 Hz, 1H) 4.21-4.41 (m, 2H) 4.92-5.06(m, 1H) 5.06-5.18 (m, 1H) 5.57 (d, J=10.61 Hz, 1H) 7.89 (s, 1H) 8.18 (d,J=3.28 Hz, 1H). [M+H] calc'd for C₁₈H₂₁FN₄O₄S, 409; found, 409.3.

Example 49(R)—N-(cyclopropylmethoxy)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol). DMF (0.5 mL),O-(cyclopropylmethyl)hydroxylamine hydrochloride (6.4 mg, 0.051 mmol),HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) andN,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and thesolution was stirred at 25° C. for 4 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 20-50%). Thefractions were collected and lyophilized to afford the title compound asa white solid (5 mg, 23%). ¹H NMR (400 MHz, CD₃OD) δ 0.16-0.24 (m, 2H)0.39-0.55 (m, 2H) 0.93 (d, J=6.57 Hz, 3H) 1.05 (d, J=6.32 Hz, 3H)1.06-1.15 (m, 1H) 2.53 (dt, J=11.24, 6.51 Hz, 1H) 3.55-3.73 (m, 2H) 4.94(d, J=11.37 Hz, 1H) 5.07 (d, J=19.20 Hz, 1H) 5.46 (d, J=18.44 Hz, 1H)7.86 (s, 1H) 8.17 (d, J=3.28 Hz, 1H). [M+H] calc'd for C₁₈H₂₁FN₄O₃, 361;found, 361.4.

PREPARATION Q: 3,3-difluorocyclopentanamine

STEP A: tert-butyl 3,3-difluorocyclopentylcarbamate

Deoxofluor™ (0.658 mL, 5.02 mmol) was added dropwise to a solution oftert-butyl 3-oxocyclopentylcarbamate (0.5 g, 2.509 mmol) in DCM (12 mL)at 0° C. After complete addition, the reaction mixture was allowed towarm up to room temperature and was stirred for 18 h. The reactionmixture was poured slowly into ice-cold aqueous NaHCO₃ (sat.). Theaqueous layer was extracted 3 times with DCM. The combined organiclayers were dried over MgSO₄, concentrated, and dried in vacuo.Purification by silica column chromatography (MeOH/DCM, 0-5%) affordedthe title compound as a yellow oil (0.52 g, 94%).

STEP B: 3,3-difluorocyclopentanamine

A mixture of tert-butyl 3,3-difluorocyclopentylcarbamate and DCM/TFA(50%, 7 mL) was stirred at 25° C. for 30 min. The reaction mixture wasconcentrated down and dried in vacuo to afford the title compound as anorange semi-solid, TFA salt (0.51 g, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ1.69-1.88 (m, 1H) 2.00-2.22 (m, 3H) 2.22-2.38 (m, 1H) 2.56 (d, J=6.32Hz, 1H) 3.71 (d, J=5.31 Hz, 1H) 8.20 (br. s., 3H).

Example 50(2R)—N-(3,3-difluorocyclopentyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol) under nitrogen. DMF (0.5 mL),3,3-difluorocyclopentanamine (11.2 mg, 0.051 mmol), HOBt (11.83 mg,0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine(9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C.for 4 h. The reaction mixture was purified via preparative mass triggerLC-MS (AcCN/H₂O, 20-50%). The fractions were collected and lyophilizedto afford the title compound as a brown oil (8 mg, 39.4%). ¹H NMR (500MHz, CD₃OD) δ 0.93 (d, J=6.83 Hz, 3H) 1.04 (dd, J=6.35, 2.93 Hz, 3H)1.62-1.80 (m, 1H) 1.87-2.02 (m, 1H) 2.14-2.28 (m, 2H) 2.35-2.58 (m, 2H)3.35 (s, 1H) 4.22-4.35 (m, 1H) 4.94-5.10 (m, 2H) 5.45 (dd, J=18.79, 5.13Hz, 1H) 7.86 (s, 1H) 8.17 (d, J=2.93 Hz, 1H). [M+H] calc'd forC₁₉H₂₁F₃N₄O₂, 395; found, 395.4.

PREPARATION R: 3-(fluoromethyl)azetidine-3-carbonitrile, TFA salt

STEP A: tert-butyl 3-cyano-3-(fluoromethyl)azetidine-1-carboxylate

To an oven-dried 25 mL round bottom flask equipped for stirring wasadded diisopropylamine (0.659 mL, 4.66 mmol) under nitrogen. THF (5 mL)was added and the colorless solution was cooled to 0° C. To thissolution was added n-BuLi (2.92 mL, 4.66 mmol) and the solution wasstirred at 0° C. for 30 min. The solution was cooled to −78° C. and asolution of tert-butyl 3-cyanoazetidine-1-carboxylate (0.5 g, 2.74 mmol)in THF (3 mL) was added and the solution was stirred at −78° C. for 30min. Bromofluoromethane (0.403 g, 3.57 mmol) was added at −78° C.dropwise. The reaction mixture was stirred for 30 min and then allowedto warm to 25° C. and stirred for 16 h. The reaction mixture wasquenched at 0° C. with aqueous NH₄Cl (5 mL) and extracted with DCM (3×).The extracts were dried over Na₂SO₄. Purification by silica columnchromatography (MeOH/DCM, 0-5%) afforded the title compound as a yellowoil (0.52 g, 94%).

STEP B: 3-(fluoromethyl)azetidine-3-carbonitrile, TFA salt

A mixture of tert-butyl 3-cyano-3-(fluoromethyl)azetidine-1-carboxylateand DCM/TFA (50%, 5 mL) at 25° C. for 30 min. The reaction mixture wasconcentrated and dried under high vacuum to afford the title compound asan orange semi solid (145 mg, 0.687 mmol, 25%). ¹H NMR (400 MHz, CDCl₃)δ 1.47 (dd, J=5.05, 2.02 Hz, 9H) 4.03 (br. s., 2H) 4.29 (br. s., 2H)4.62 (br. s., 1H) 4.73 (br. s., 1H).

Example 51(R)-3-(fluoromethyl)-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

To an 8 mL scintillation vial equipped for stirring was added(R)-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid (80 mg, 0.293 mmol) under nitrogen. DMF (0.5 mL),3-(fluoromethyl)azetidine-3-carbonitrile (93 mg, 0.439 mmol), HOBt (67.2mg, 0.439 mmol), EDC (84 mg, 0.439 mmol) and N,N-dimethylpyridin-4-amine(53.6 mg, 0.439 mmol) were added and the solution was stirred at 25° C.for 4 h. The reaction mixture was purified via preparative mass triggerLC-MS (AcCN/H₂O, 20-50%). The fractions were collected and lyophilizedto afford the title compound as a white solid (34.5 mg, 25.3%). ¹H NMR(400 MHz, DMSO-d₆) δ 0.78 (dd, J=6.57, 3.79 Hz, 3H) 0.97 (dd, J=12.88,6.32 Hz, 3H) 2.30-2.41 (m, 1H) 3.99 (dd, J=9.98, 4.42 Hz, 1H) 4.22 (d,J=9.35 Hz, 2H) 4.36 (s, 1H) 4.62-4.71 (m, 1H) 4.76-4.88 (m, 2H)4.87-5.03 (m, 1H) 5.02-5.09 (m, 1H) 7.09 (t, J=4.80 Hz, 1H) 7.88 (dd,J=5.56, 2.27 Hz, 1H) 8.27 (t, J=5.31 Hz, 1H) 12.25 (d, J=8.84 Hz, 1H).[M+H] calc'd for C₁₉H₂₀FN₅O₂, 370; found, 370.5.

PREPARATION S: 3-cyano-3-methylazetidine, TFA salt

STEP A: tert-butyl 3-cyano-3-methylazetidine-1-carboxylate

To an oven-dried 25 mL round bottom flask equipped for stirring wasadded diisopropylamine (1.318 mL, 9.33 mmol) under nitrogen. THF (10 mL)was added and the colorless solution was cooled to 0° C. n-BuLi inhexanes (1.6N, 5.83 mL, 9.33 mmol) was added dropwise and the solutionwas stirred at 0° C. for 30 min. The solution was cooled to −78° C. anda solution of tert-butyl 3-cyanoazetidine-1-carboxylate (1 g, 5.49 mmol)in THF (3 mL) was added and the solution was stirred at −78° C. for 30min. Iodomethane (0.445 mL, 7.13 mmol) was added dropwise at −78° C. Thereaction mixture was stirred for 30 min; it was then allowed to slowlywarm up to 25° C. and was stirred for 16 h. The reaction mixture wasquenched at 0° C. with aqueous ammonium chloride (5 mL) and wasextracted with DCM (3 times). The extracts were dried over Na₂SO₄.Purification by silica column chromatography (MeOH/DCM, 0-5%) affordedthe title compound as a yellow oil (0.35 g, 32%). ¹H NMR (500 MHz,CDCl₃) δ 1.45 (s, 9H) 1.67 (s, 3H) 3.80 (d, J=8.30 Hz, 2H) 4.29 (d,J=8.79 Hz, 2H).

STEP B: 3-cyano-3-methylazetidine, TFA salt

A mixture of tert-butyl 3-cyano-3-methylazetidine-1-carboxylate (0.345g, 1.758 mmol) and DCM/TFA (50%, 7 mL) was stirred at 25° C. for 30 min.The reaction mixture was concentrated and dried in vacuo to afford thetitle compound as an orange semi-solid (0.22 g, 1.139 mmol, 64.8%). ¹HNMR (400 MHz, DMSO-d₆) δ 1.65 (s, 3H) 3.92 (d, J=11.12 Hz, 2H) 4.34 (d,J=11.12 Hz, 2H) 9.23 (br. s., 2H).

Example 52(R)-1-(2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)-3-methylazetidine-3-carbonitrile

To an 8 mL scintillation vial equipped for stirring was added(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol). DMF (0.5 mL), 3-cyano-3-methylazetidine (15mg, 0.077 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol)and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and thesolution was stirred at 25° C. for 4 h. The reaction mixture waspurified via preparative mass trigger LC-MS (AcCN/H₂O, 20-50%). Thefractions were collected and lyophilized to afford the title compound asa white solid (9 mg, 47.3%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.79 (dd,J=6.69, 2.91 Hz, 3H) 0.96 (dd, J=9.09, 6.57 Hz, 3H) 1.41-1.73 (m, 3H)2.26-2.44 (m, 1H) 3.85 (dd, J=15.66, 9.85 Hz, 1H) 4.06 (d, J=9.35 Hz,2H) 4.61 (s, 1H) 4.88 (dd, J=19.20, 6.82 Hz, 1H) 5.03 (d, J=11.12 Hz,1H) 5.07-5.18 (m, 1H) 7.99 (t, J=3.16 Hz, 1H) 8.25 (t, J=2.65 Hz, 1H)12.40 (br. s., 1H). [M+H] calc'd for C₁₉H₂₀FN₅O₂, 370; found, 370.5

Example 53(R)-3-methyl-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

To an 8 mL scintillation vial equipped for stirring was added(R)-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid (80 mg, 0.293 mmol). DMF (0.5 mL), 3-cyano-3-methylazetidine (85mg, 0.439 mmol), HOBt (67.2 mg, 0.439 mmol), EDC (84 mg, 0.439 mmol) andN,N-dimethylpyridin-4-amine (53.6 mg, 0.439 mmol) were added and thesolution was stirred at 25° C. for 4 h. The fractions were collected andlyophilized to afford the title compound as a white solid (31.5 mg,30.6%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.78 (dd, J=6.82, 3.28 Hz, 3H) 0.96(dd, J=8.59, 6.32 Hz, 3H) 1.44-1.68 (m, 3H) 2.26-2.44 (m, 1H) 3.84 (dd,J=9.47, 5.18 Hz, 1H) 3.99-4.14 (m, 1H) 4.21 (dd, J=9.47, 5.68 Hz, 1H)4.34-4.65 (m, 1H) 4.85 (dd, J=19.45, 5.56 Hz, 1H) 4.96-5.11 (m, 2H) 7.08(d, J=5.05 Hz, 1H) 7.86 (d, J=4.04 Hz, 1H) 8.26 (dd, J=4.80, 3.28 Hz,1H) 12.22 (br. s., 1H). [M+H] calc'd for C₁₉H₂₁N₅O₂, 352; found, 352.5.

PREPARATION T:(R)-2-((3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)butanoicacid compound with 2,2,2-trifluoroacetic acid (1:1)

STEP A: (R)-1-tert-butyl 3-methyl4-((1-tert-butoxy-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate

Sodium triacetoxyborohydride (9.86 mmol) and (R)-tert-butyl2-aminobutanoate hydrochloride (5.59 mmol) were added to a 100 mL roundbottom flask, followed by DCE (20 mL). The reaction mixture was stirredat room temperature for 30 min and cooled to 0° C. A solution of1-tert-butyl 3-methyl4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (3.29 mmol) in DCE(20 mL) was added. The reaction mixture was stirred at 0° C. for 30 minand at room temperature for 3 h. Purification by silica columnchromatography (EtOAc/DCM, 0-10%) afforded the title compound as ayellow oil (1.4 g, 95%). [M+H] calc'd for C₂₃H₃₃N₃O₆, 448; found, 448.6.

STEP B:(R)-2-((3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)butanoicacid compound with 2,2,2-trifluoroacetic acid (1:1)

To a 100 mL round bottom flask equipped for stirring was added(R)-1-tert-butyl 3-methyl4-((1-tert-butoxy-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate(1.45 g, 3.24 mmol) and DCM (10 mL). TFA (10 mL) was added and thereaction mixture was stirred at room temperature for 30 min. Thereaction mixture was concentrated and dried in vacuo to afford the titlecompound as a yellow oil (1.3 g, 99%) (TFA salt). [M+H] calc'd forC₁₄H₁₇N₃O₄, 292; found, 292.6.

ExampleS 54 to 74

Compounds in Examples 54 to 74 were made in accordance with thefollowing General Procedure A.

To an 8 mL scintillation vial equipped for stirring was added(R)-2-((3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)butanoicacid (43.4 mg, 0.149 mmol) and HATU (68.0 mg, 0.179 mmol). THF (2 mL),4-methylmorpholine (0.049 mL, 0.447 mmol) and an appropriate amine,NHR₁R₂ (0.447 mmol) were added. The suspension was stirred at roomtemperature for 4 h and then concentrated to afford crude intermediateA, which was subsequently re-dissolved in MeOH (1 mL). Aqueous NaOH(12N, 2 mL) was added and the reaction mixture was stirred at 53° C. for16 h. This residue was purified via preparative mass trigger LC-MS(AcCN/H₂O, 1-50%). The fractions were collected, concentrated, and driedin vacuo to afford intermediate B, which was cyclized in a mixture ofTHF (2 mL), HATU (68.0 mg, 0.179 mmol) and 4-methylmorpholine (0.049 mL,0.447 mmol) at room temperature for 4 to 16 h. The product was purifiedvia preparative mass trigger LC-MS (AcCN/H₂O, 1-50%). The fractions werecollected, concentrated, and dried in vacuo to afford the titlecompound.

Example 54(R)-4-(1-morpholino-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using morpholine as the amine, NHR₁R₂ (2.1 mg, 4.2% for 3 steps). ¹H NMR(400 MHz, CD₃OD) δ 0.96 (t, J=7.45 Hz, 3H) 1.99-2.13 (m, 2H) 3.43-3.51(m, 1H) 3.53-3.62 (m, 2H) 3.62-3.73 (m, 4H) 5.06 (d, J=10.86 Hz, 2H)5.66-5.78 (m, 1H) 7.21 (d, J=5.31 Hz, 1H) 7.86 (s, 1H) 8.32 (d, J=5.31Hz, 1H). [M+H] calc'd for C₁₇H₂₀N₄O₃, 329; found, 329.6.

Example 55(R)-4-(1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using 1-methylpiperazine as the amine, NHR₁R₂ (3.2 mg, 6.3% for 3steps). ¹H NMR (400 MHz, CD₃OD) δ −0.52 (t, J=7.33 Hz, 3H) 0.42-0.60 (m,2H) 1.33 (s, 3H) 1.43 (d, J=12.88 Hz, 3H) 1.58-1.74 (m, 1H) 1.84-1.93(m, 3H) 1.93-2.05 (m, 2H) 4.28 (s, 1H) 5.64 (d, J=5.31 Hz, 1H) 6.34 (s,1H) 6.81 (d, J=5.05 Hz, 1H). [M+H] calc'd for C₁₈H₂₃N₅O₂, 342; found,342.6.

Example 564-((2R)-1-(3-hydroxypyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using 1-pyrrolidin-3-ol as the amine, NHR₁R₂ (16 mg, 32.7%, 3 steps). ¹HNMR (400 MHz, CD₃OD) δ 0.90-1.08 (m, 3H) 1.82-2.12 (m, 4H) 2.91 (s, 1H)3.41-3.67 (m, 2H) 3.74 (t, J=11.60 Hz, 2H) 4.28-4.50 (m, 1H) 4.85-4.98(m, 2H) 7.13 (d, J=5.31 Hz, 1H) 7.81 (t, J=3.41 Hz, 1H) 8.28 (d, J=5.81Hz, 1H). [M+H] calc'd for C₁₇H₂₀N₄O₃, 329; found, 329.6.

Example 57(R)—N-cyclopentyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using cyclopentanamine as NHR₁R₂ (6.3 mg, 13%, 3 steps). ¹H NMR (400MHz, CD₃OD) δ 0.98 (q, J=7.50 Hz, 3H) 1.38-1.52 (m, 2H) 1.52-1.63 (m,2H) 1.63-1.79 (m, 2H) 1.80-2.01 (m, 2H) 2.12-2.17 (m, 2H) 3.99-4.19 (m,1H) 5.23 (dd, J=9.35, 6.82 Hz, 1H) 5.27-5.37 (m, 1H) 5.48 (s, 2H) 7.23(d, J=5.56 Hz, 1H) 7.85 (s, 1H) 8.32 (d, J=5.56 Hz, 1H). [M+H] calc'dfor C₁₈H₂₂N₄O₂, 327; found, 327.6.

Example 584-((2R)-1-(3-(4-fluorophenyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using 3-(4-fluorophenyl)pyrrolidine as the amine, NHR₁R₂ (14 mg, 23.1%,3 steps). ¹H NMR (400 MHz, CD₃OD) δ 0.89-1.06 (m, 3H) 1.80 (s, 2H)2.19-2.39 (m, 2H) 3.33-3.55 (m, 2H) 3.56-3.65 (m, 1H) 3.68-3.83 (m, 1H)3.84-3.96 (m, 1H) 3.98-4.24 (m, 1H) 5.03-5.35 (m, 2H) 6.68-6.83 (m, 1H)6.86-6.99 (m, 1H) 6.99-7.09 (m, 2H) 7.10-7.37 (m, 1H) 7.78-7.95 (m, 1H)8.34 (d, J=5.31 Hz, 1H). [M+H] calc'd for C₂₃H₂₃FN₄O₂, 407; found,407.6.

Example 594-((2R)-1-(3-(dimethylamino)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using N,N-dimethylpyrrolidin-3-amine as NHR₁R₂ (20 mg, 37.8%, 3 steps).¹H NMR (400 MHz, CD₃OD) δ 0.87-1.05 (m, 3H) 1.88-2.12 (m, 2H) 2.12-2.26(m, 1H) 2.43 (d, J=8.84 Hz, 1H) 2.64-2.85 (m, 3H) 2.85-3.02 (m, 4H)3.43-3.68 (m, 1H) 3.68-3.90 (m, 1H) 3.90-4.03 (m, 1H) 4.03-4.26 (m, 0H)4.99-5.19 (m, 2H) 5.51-5.71 (m, 1H) 7.08-7.25 (m, 1H) 7.79-7.92 (m, 1H)8.32 (d, J=5.31 Hz, 1H). [M+H] calc'd for C₁₉H₂₅N₅O₂, 356; found, 356.6.

Example 604-((2R)-1-(3-(methoxymethyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using 3-(methoxymethyl)pyrrolidine as the amine, NHR₁R₂ (12 mg, 22.6%, 3steps). ¹H NMR (400 MHz, CD₃OD) δ 0.98 (td, J=7.39, 1.89 Hz, 3H)1.62-1.80 (m, 1H) 1.85-2.12 (m, 5H) 2.35-2.60 (m, 1H) 3.32-3.35 (m, 3H)3.37-3.51 (m, 2H) 3.52-3.70 (m, 1H) 3.70-3.85 (m, 1H) 5.06-5.29 (m, 2H)5.53-5.69 (m, 1H) 7.19-7.35 (m, 1H) 7.89 (s, 1H) 8.34 (d, J=5.31 Hz,1H). [M+H] calc'd for C₁₉H₂₄N₄O₃, 357; found, 357.6.

Example 614-((2R)-1-(3-methylpiperidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using 3-methylpiperidine as the amine, NHR₁R₂ (10.8 mg, 21.3%, 3 steps).¹H NMR (400 MHz, CD₃OD) δ 0.71 (d, J=6.32 Hz, 1H) 0.83-1.04 (m, 7H) 1.14(br. s., 1H) 1.68 (d, J=10.36 Hz, 2H) 1.81-2.07 (m, 2H) 2.54-2.77 (m,1H) 2.95-3.10 (m, 1H) 4.01 (d, J=14.65 Hz, 1H) 4.20-4.51 (m, 1H)4.89-5.04 (m, 1H) 5.04-5.18 (m, 1H) 5.71-5.87 (m, 1H) 7.19-7.26 (m, 1H)7.89 (d, J=4.80 Hz, 1H) 8.33 (d, J=5.31 Hz, 1H). [M+H] calc'd forC₁₉H₂₄N₄O₂, 341; found, 341.6.

Example 62(R)-4-(1-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using 2-(piperidin-4-yl)propan-2-ol as the amine, NHR₁R₂ (10 mg, 17.5%,3 steps). ¹H NMR (400 MHz, CD₃OD) δ 0.80 (s, 3H) 0.85 (s, 3H) 0.92-1.00(m, 3H) 1.43-1.56 (m, 1H) 1.60 (d, J=13.89 Hz, 1H) 1.77 (d, J=12.88 Hz,1H) 1.83-1.95 (m, 2H) 1.95-2.06 (m, 2H) 2.48-2.66 (m, 1H) 2.86-3.07 (m,1H) 4.16 (d, J=15.66 Hz, 1H) 4.64 (d, J=14.15 Hz, 1H) 4.87-5.03 (m, 1H)5.03-5.19 (m, 1H) 5.75 (t, J=7.58 Hz, 1H) 7.23 (d, J=5.31 Hz, 1H)7.81-7.94 (m, 1H) 8.23-8.37 (m, 1H). [M+H] calc'd for C₂₁H₂₈N₄O₃, 385;found, 385.6.

Example 63(R)-4-(1-(4-(methylsulfonyl)piperazin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using 1-(methylsulfonyl)piperazine as the amine, NHR₁R₂ (7.3 mg, 12.1%,3 steps). ¹H NMR (400 MHz, CD₃OD) δ 0.97 (t, J=7.45 Hz, 3H) 1.85-2.06(m, 2H) 2.75 (s, 3H) 3.06 (br.s., 1H) 3.09-3.19 (m, 1H) 3.26 (dd,J=3.16, 1.64 Hz, 2H) 3.68 (br. s., 1H) 3.74 (br. s., 1H) 3.79 (br. s.,2H) 4.96-5.14 (m, 2H) 5.76 (dd, J=8.34, 6.82 Hz, 1H) 7.23 (d, J=5.31 Hz,1H) 7.89 (s, 1H) 8.32 (d, J=5.56 Hz, 1H). [M+H] calc'd for C₁₈H₂₃N₅O₄S,406; found, 406.6.

Example 64(R)-4-(1-oxo-1-(4-(pyridin-2-yl)piperazin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

The title compound was prepared in accordance with General Procedure A,using 1-(pyridin-2-yl)piperazine as the amine, NHR₁R₂ (5.2%, 3 steps).¹H NMR (400 MHz, CD₃OD) δ 0.88-1.04 (m, 3H) 1.93-2.09 (m, 2H) 3.54-3.63(m, 1H) 3.69 (d, J=11.12 Hz, 1H) 3.72-3.87 (m, 3H) 3.87-3.95 (m, 2H)3.98 (br. s., 1H) 5.05 (q, J=19.28 Hz, 2H) 5.80 (dd, J=8.34, 6.82 Hz,1H) 6.99 (t, J=6.69 Hz, 1H) 7.14 (d, J=5.05 Hz, 1H) 7.33 (d, J=9.35 Hz,1H) 7.84 (s, 1H) 7.92 (dd, J=6.32, 1.26 Hz, 1H) 8.01 (ddd, J=9.22, 7.20,1.77 Hz, 1H) 8.29 (d, J=5.30 Hz, 1H). [M+H] calc'd for C₂₂H₂₄N₆O₂, 405;found, 405.6.

Example 65(R)—N-cyclopropyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using cyclopropanamine as NHR₁R₂ (1.7 mg, 2.2%, 3 steps). ¹H NMR (400MHz, CD₃OD) δ 0.44-0.53 (m, 2H) 0.96 (t, J=7.33 Hz, 3H) 2.66-2.73 (m,4H) 3.71-3.81 (m, 1H) 5.05-5.29 (m, 1H) 5.44-5.52 (m, 2H) 7.52 (dd,J=8.46, 4.42 Hz, 1H) 8.43 (dd, J=8.34, 1.26 Hz, 1H) 8.73 (d, J=3.54 Hz,1H). [M+H] calc'd for C₁₆H₁₈N₄O₂, 299; found, 299.6.

Example 66(R)—N-(cyclopropylmethyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using cyclopropylmethanamine as NHR₁R₂ (9 mg, 11.2%, 3 steps). ¹H NMR(400 MHz, CD₃OD) δ 0.13-0.22 (m, 2H) 0.40-0.48 (m, 2H) 0.90-1.06 (m, 4H)1.86-2.01 (m, 1H) 2.05-2.16 (m, 1H) 3.06 (d, J=6.82 Hz, 2H) 5.04-5.13(m, 1H) 5.13-5.22 (m, 1H) 5.28 (dd, J=9.47, 6.69 Hz, 1H) 7.14 (d, J=5.05Hz, 1H) 7.81 (s, 1H) 8.29 (d, J=4.80 Hz, 1H). [M+H] calc'd forC₁₇H₂₀N₄O₂, 313; found, 313.6.

Example 67(R)—N-isobutyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using 2-methylpropan-1-amine as NHR₁R₂ (5.2 mg, 6.4%, 3 steps). ¹H NMR(400 MHz, CD₃OD) δ 0.87 (d, J=6.32 Hz, 6H) 0.99 (t, J=7.45 Hz, 3H) 1.78(dt, J=13.58, 6.73 Hz, 1H) 1.95 (ddd, J=14.15, 9.35, 7.33 Hz, 1H) 2.11(dt, J=14.65, 7.33 Hz, 1H) 3.01 (dd, J=6.95, 1.64 Hz, 2H) 5.04-5.19 (m,1H) 5.19-5.32 (m, 2H) 7.24 (d, J=5.31 Hz, 1H) 7.87 (s, 1H) 8.33 (d,J=5.56 Hz, 1H). [M+H] calc'd for C₁₇H₂₂N₄O₂, 315; found, 315.6.

Example 68(R)—N-isobutyl-N-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using N,2-dimethylpropan-1-amine as NHR₁R₂ (10.5 mg, 12.4%, 3 steps). ¹HNMR (400 MHz, CD₃OD) δ 0.85 (td, J=6.95, 6.06 Hz, 5H) 0.90-1.09 (m, 4H)1.84-2.09 (m, 4H) 2.94 (s, 1H) 3.05-3.16 (m, 2H) 3.24 (dd, J=7.45, 3.92Hz, 1H) 3.46 (dd, J=14.27, 8.21 Hz, 1H) 5.11 (s, 1H) 5.68-5.90 (m, 1H)7.15-7.33 (m, 1H) 7.88 (d, J=3.28 Hz, 1H) 8.32 (dd, J=5.31, 3.03 Hz,1H). [M+H] calc'd for C₁₈H₂₄N₄O₂, 329; found, 329.6.

Examples 69(2R)—N-(1-hydroxypropan-2-yl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using 2-aminopropan-1-ol as the amine, NHR₁R₂ (27 mg, 33.1%, 3 steps).¹H NMR (400 MHz, CD₃OD) δ 0.88-1.03 (m, 2H) 1.04-1.19 (m, 2H) 1.85-2.00(m, 1H) 2.04-2.17 (m, 1H) 2.75-2.87 (m, 1H) 2.87-3.05 (m, 1H) 3.05-3.21(m, 1H) 3.38-3.56 (m, 2H) 3.93-4.05 (m, 1H) 4.97-5.13 (m, 1H) 5.13-5.32(m, 1H) 7.05-7.19 (m, 1H) 7.80 (s, 1H) 8.27 (d, J=5.05 Hz, 1H). [M+H]calc'd for C₁₆H₂₀N₄O₃, 317; found, 317.6.

Example 70(R)—N-(2-hydroxy-2-methylpropyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using 1-amino-2-methylpropan-2-ol as the amine, NHR₁R₂ (12 mg, 14.1%, 3steps). ¹H NMR (400 MHz, CD₃OD) δ 1.00 (t, J=7.33 Hz, 3H) 1.13 (d,J=2.27 Hz, 6H) 1.90-2.02 (m, 1H) 2.08-2.22 (m, 1H) 3.15-3.26 (m, 2H)5.07-5.21 (m, 1H) 5.21-5.37 (m, 2H) 7.28 (d, J=5.56 Hz, 1H) 7.89 (s, 1H)8.34 (d, J=5.56 Hz, 1H). [M+H] calc'd for C₁₇H₂₂N₄O₃, 331; found, 331.6.

Example 71(R)—N—((S)-2,3-dihydroxypropyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using (S)-3-aminopropane-1,2-diol as the amine, NHR₁R₂ (1.9 mg, 2.2%, 3steps). ¹H NMR (400 MHz, CD₃OD) δ 0.98 (t, J=7.33 Hz, 2H) 1.29 (s, 1H)1.86-2.02 (m, 1H) 2.06-2.19 (m, 1H) 2.70 (s, 1H) 3.08-3.29 (m, 1H)3.40-3.51 (m, 2H) 3.61-3.77 (m, 1H) 5.02-5.32 (m, 3H) 7.16 (d, J=4.80Hz, 1H) 7.82 (s, 1H) 8.31 (br. s., 1H). [M+H] calc'd for C₁₆H₂₀N₄O₄,333; found, 333.6.

Example 72(R)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-phenylbutanamide

The title compound was prepared in accordance with General Procedure A,using aniline as the amine, NHR₁R₂ (5 mg, 5.8%, 3 steps). ¹H NMR (400MHz, CD₃OD) δ 1.05 (t, J=7.33 Hz, 3H) 2.04-2.13 (m, 1H) 2.13-2.28 (m,1H) 5.11-5.27 (m, 1H) 5.31-5.47 (m, 2H) 7.00-7.14 (m, 1H) 7.21 (d,J=5.31 Hz, 1H) 7.23-7.36 (m, 2H) 7.54 (dd, J=8.59, 1.01 Hz, 2H) 7.85 (s,1H) 8.32 (br. s., 1H). [M+H] calc'd for C₁₉H₁₈N₄O₂, 335; found, 335.6.

Example 73(R)—N-(1-(methylsulfonyl)piperidin-4-yl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

The title compound was prepared in accordance with General Procedure A,using 1-(methylsulfonyl)piperidin-4-amine as NHR₁R₂ (20 mg, 18.5%, 3steps). ¹H NMR (400 MHz, CD₃OD) δ 0.99 (t, J=7.33 Hz, 2H) 1.26-1.42 (m,2H) 1.46-1.67 (m, 2H) 1.84-2.00 (m, 2H) 2.06-2.25 (m, 1H) 2.76-2.94 (m,4H) 3.22 (quin, J=6.95 Hz, 1H) 3.33-3.39 (m, 2H) 3.59-3.88 (m, 3H)5.11-5.27 (m, 1H) 7.29 (d, J=5.31 Hz, 1H) 7.89 (s, 1H) 8.35 (d, J=5.31Hz, 1H). [M+H] calc'd for C₁₉H₂₅N₅O₄S, 420; found, 420.6.

Example 74(2R)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-((tetrahydrofuran-2-yl)methyl)butanamide

The title compound was prepared in accordance with General Procedure A,using (tetrahydrofuran-2-yl)methanamine as NHR₁R₂ (3.1 mg, 3.5%, 3steps). ¹H NMR (400 MHz, CD₃OD) δ 0.98 (td, J=7.39, 1.64 Hz, 3H) 1.55(s, 1H) 1.75-2.02 (m, 4H) 2.12 (dt, J=14.46, 7.29 Hz, 1H) 3.18-3.30 (m,2H) 3.57-3.73 (m, 1H) 3.73-3.87 (m, 1H) 3.96 (dd, J=11.12, 6.32 Hz, 1H)5.01-5.22 (m, 2H) 5.29 (dt, J=9.35, 6.82 Hz, 1H) 7.16 (d, J=5.05 Hz, 1H)7.83 (s, 1H) 8.30 (d, J=5.05 Hz, 1H). [M+H] calc'd for C₁₈H₂₂N₄O₃, 343;found, 343.6.

Example 75(2R)—N-(1-cyanoethyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide

(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDChydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL).2-Aminopropanenitrile hydrochloride (8.23 mg, 0.077 mmol) and4-methylmorpholine (0.023 mL, 0.206 mmol) were added and the reactionmixture was stirred at room temperature for 2 h. Following reaction, theproduct was purified by preparative HPLC (10-55% AcCN/H₂O with 0.035%TFA), concentrated in vacuo, and lyophilized to afford the titlecompound as a white solid (11 mg, 62%). ¹H NMR (500 MHz, DMSO-d₆) δ1.20-1.26 (m, 3H), 1.32-1.39 (m, 3H), 1.77-1.82 (m, 3H), 2.76-2.84 (m,1H), 5.06-5.22 (m, 1H), 5.36-5.44 (m, 2H), 5.77 (dd, J=19.0, 2.0 Hz,1H), 8.38 (dd, J=10.5, 2.0 Hz, 1H), 8.65 (t, J=3.0 Hz, 1H), 9.47 (d,J=2.0 Hz, 1H), 12.78 (br d, J=7.5 Hz, 1H). [M+H] calc'd for C₁₇H₁₈FN₅O₂,344; found, 344.

Example 76(R)-4-(1-(3,3-difluoroazetidin-1-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDChydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL).3,3-Difluoroazetidine hydrochloride (10.0 mg, 0.077 mmol) and4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reactionmixture was stirred at room temperature for 2 h. Following reaction, theproduct was purified by preparative HPLC (10-60% AcCN/H₂O with 0.035%TFA), concentrated in vacuo, and lyophilized to afford the titlecompound as a white solid (10 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δ 0.80(d, J=6.0 Hz, 3H), 0.96 (d, J=6.0 Hz, 3H), 2.30-2.41 (m, 1H), 4.26-4.36(m, 2H), 4.41-4.51 (m, 1H), 4.70-4.79 (m, 1H), 5.00 (AB q, J=104.5, 22.0Hz, 2H), 5.07 (d, J=23.0 Hz, 1H), 7.99 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5Hz, 1H), 12.40 (s, 1H). [M+H] calc'd for C₁₇H₁₇F₃N₄O₂, 367; found, 367.

Example 77(R)-4-(1-(1,1-dioxidothiazolidin-3-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDChydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL).Thiazolidine 1,1-dioxide hydrochloride (12.17 mg, 0.077 mmol) and4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reactionmixture was stirred at room temperature for 2 h. The product waspurified by preparative HPLC (10-45% AcCN/H₂O with 0.035% TFA),concentrated in vacuo, and lyophilized to afford the title compound as awhite solid (8.8 mg, 43%). ¹H NMR (500 MHz, DMSO-d₆) δ 0.76-0.81 (m,3H), 0.95 (d, J=6.5 Hz, 3H), 2.41-2.50 (m, 1H), 3.35-3.45 (m, 2H),3.80-3.89 (m, 2H), 4.49-4.91 (m, 4H), 5.18-5.42 (m, 1H), 8.01 (d, J=2.5Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.43 (s, 1H). [M+H] calc'd forC₁₇H₁₉FN₄O₄S, 395; found, 395.

Example 78(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N,3-dimethyl-N-(2-(methylsulfonyl)ethyl)butanamide

(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDChydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL).N-methyl-2-(methylsulfonyl)ethanamine (10.60 mg, 0.077 mmol) and4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reactionmixture was stirred at room temperature for 2 h. The product waspurified by preparative HPLC (10-45% AcCN/H₂O with 0.035% TFA),concentrated in vacuo, and lyophilized to afford the title compound as awhite solid (12 mg, 57% yield). ¹H NMR (500 MHz, CD₃OD) δ 0.77 (d, J=6.5Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 2.41-2.49 (m, 1H), 2.97 (s, 3H), 3.05(s, 3H), 3.36 (t, J=6.5 Hz, 2H), 3.78 (t, J=6.5 Hz, 2H), 4.81-4.96 (m,2H), 5.36 (d, J=11.0 Hz, 1H), 7.97 (d, J=2.5 Hz, 1H), 8.23 (d, J=2.5 Hz,1H), 12.39 (s, 1H). [M+H] calc'd for C₁₈H₂₃FN₄O₄S, 411; found, 411.

Example 79(R)—N-(cyanomethyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N,3-dimethylbutanamide

(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDChydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL).2-(Methylamino)acetonitrile (5.41 mg, 0.077 mmol) and 4-methylmorpholine(0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirredat room temperature for 2 h. The product was purified by preparativeHPLC (10-55% AcCN/H₂O with 0.035% TFA), concentrated in vacuo, andlyophilized to afford the title compound as a pale yellow solid (7.8 mg,44%). ¹H NMR (500 MHz, DMSO-d₆) δ 0.78 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5Hz, 3H), 2.44-2.51 (m, 1H), 3.12 (s, 3H), 4.39 (AB q, J=84.5, 17.5 Hz,2H), 4.89 (d, J=5.5 Hz, 2H), 5.42 (d, J=11.0 Hz, 1H), 8.00 (d, J=2.5 Hz,1H), 8.24 (d, J=2.5 Hz, 1H), 12.43 (s, 1H). [M+H] calc'd forC₁₇H₁₈FN₅O₂, 344; found, 344.

Example 80(R)-4-(1-(3-(difluoromethyl)azetidin-1-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDChydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL).3-(Difluoromethyl)azetidine (8.27 mg, 0.077 mmol) and 4-methylmorpholine(0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirredat room temperature for 2 h. The product was purified by preparativeHPLC (10-60% AcCN/H₂O with 0.035% TFA), concentrated in vacuo, andlyophilized to afford the title compound as a white solid (9.8 mg, 50%).¹H NMR (500 MHz, DMSO-d₆) δ 0.78 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.0 Hz,3H), 2.31-2.39 (m, 1H), 2.99-3.15 (m, 1H), 3.77-4.35 (m, 4H), 4.82-5.11(m, 3H), 6.10-6.41 (m, 1H), 7.98 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz,1H), 12.39 (s, 1H). [M+H] calc'd for C₁₈H₁₉F₃N₄O₂, 381; found, 381.

PREPARATION U: 4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid

STEP A: 3-Iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde

To a solution of 1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (2.0 g, 13.7mmol) in EtOH (40 mL) was added iodine (4.17 g, 16.4 mmol), sodiumiodide (2.46 g, 16.4 mmol), and aqueous NaOH (1N, 16 mL). After stirringfor 4 h at room temperature, the reaction mixture was diluted with water(200 mL), and the orange precipitate was collected by filtration anddried under vacuum. The solid was dissolved in DMF (20 mL); sodiumhydride (60%, 660 mg, 16.4 mmol) was slowly added, and after stirringthe deep red solution at room temperature for 30 min, tosyl chloride(2.87 g, 15.1 mmol) was added. The reaction mixture was stirred for anadditional 2 h at room temperature, and was then diluted with EtOAc andquenched with water. The organics were separated, washed with aqueousNaHSO₃ (0.1 N) and brine, dried over MgSO₄, and concentrated in vacuo.Purification by silica gel chromatography (3:1:1 hexane/DCM/EtOAc) gavethe title compound as a yellow solid (3.48 g, 60%). ¹H NMR (500 MHz,DMSO-d₆) δ 2.33 (s, 3H), 7.43 (d, J=8.5 Hz, 2H), 7.63 (d, J=5.0 Hz, 1H),8.03 (d, J=8.5 Hz, 2H), 8.39 (s, 1H), 8.60 (d, J=5.0 Hz, 1H), 11.31 (s,1H). [M+H] calc'd for C₁₅H₁₁N₂O₃S, 427; found, 427.

STEP B: 4-Formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Lithium chloride (358 mg, 8.45 mmol) and lithium formate monohydrate(591 mg, 8.45 mmol) were combined in a dry sealable tube under nitrogen.DMF (12 mL), 3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(1.2 g, 2.82 mmol), acetic anhydride (532 mL, 5.63 mmol) and palladiumacetate (63 mg, 0.28 mmol) were added. DIPEA (981 μL) was added, and thereaction tube was sealed and heated at 56° C. for 4 h. The reactionmixture was taken up in MeOH/DCM (20%) and filtered to remove theinsoluble black carbon material. The yellow solution was concentrated invacuo, dissolved in MeOH/DCM (10%), and washed with aqueous HCl (0.1N).The aqueous layer was extracted twice with MeOH/DCM (10%). The organicswere combined, dried over MgSO₄, and concentrated in vacuo. Purificationby silica gel chromatography (10-15% MeOH/DCM) gave the title compoundas a tan solid (866 mg, 89%). ¹H NMR (500 MHz, DMSO-d₆) δ 2.35 (s, 3H),7.45 (d, J=8.5 Hz, 2H), 7.62 (d, J=5.0 Hz, 1H), 8.11 (d, J=8.5 Hz, 2H),8.58-8.62 (m, 2H), 11.02 (s, 1H), 13.20 (br s, 1H). [M+H] calc'd forC₁₆H₁₂N₂O₅S, 345; found, 345.

PREPARATION V:(R)-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid

STEP A: (R)-tert-butyl3-methyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate

Sodium triacetoxyborohydride (603 mg, 2.85 mmol) and D-valine-tert-butylester HCl salt (597 mg, 2.85 mmol) were combined in DCM (15 mL). Thereaction mixture was stirred for 20 min at room temperature and thencooled to 0° C. 4-Formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylicacid (700 mg, 2.03 mmol) was added, and the solution was stirred for 1h. The solution was concentrated in vacuo to give a white foam, whichwas re-dissolved in THF (40 mL). HATU (1.16 g, 3.05 mmol) andN-methylmorpholine (339 μL, 3.05 mmol) were added, and the reactionmixture was stirred at 52° C. for 2 h. Additional HATU (580 mg, 1.53mmol) and N-methylmorpholine (170 μL, 1.53 mmol) were added, and thereaction mixture was stirred for an additional 2 h at 52° C. Thesolution was subsequently cooled, diluted with EtOAc, and washed withbrine. The organics were dried over MgSO₄ and concentrated in vacuo.Purification by silica gel chromatography (1:2:2 EtOAc/Hexanes/DCM) gavethe title compound as a yellow oil, which solidified upon sitting (840mg, 85%). ¹H NMR (500 MHz, CDCl₃) δ 0.86 (d, J=7.0 Hz, 3H), 1.08 (d,J=7.0 Hz, 3H), 1.42 (s, 9H), 2.25-2.34 (m, 1H), 2.35 (s, 3H), 4.77-5.14(m, 3H), 7.05 (d, J=5.0 Hz, 1H), 7.28 (d, J=7.5 Hz, 2H), 8.05-8.10 (m,3H), 8.45 (d, J=5.0 Hz, 1H). [M+H] calc'd for C₂₅H₂₉N₃O₅S, 484; found,484.

STEP B:(R)-3-Methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid

A mixture of (R)-tert-Butyl3-methyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate(840 mg, 1.74 mmol), MeOH (4 mL), and aqueous NaOH (1N, 2 mL) wasstirred for 40 min at room temperature. The material was diluted withDCM and washed with brine. The organics were dried over MgSO₄ andconcentrated in vacuo. Purification by silica gel chromatography (5%MeOH/DCM) gave a yellow oil (390 mg), which dissolved in TFA/DCM (50%)and stirred at room temperature for 1 h. The solution was concentratedand dried under vacuum to give the title compound as a tan solid (320mg, 67%). ¹H NMR (500 MHz, CD₃OD) δ 0.88 (d, J=7.0 Hz, 3H), 1.10 (d,J=7.0 Hz, 3H), 2.35-2.44 (m, 1H), 4.95-5.33 (m, 3H), 7.34 (d, J=6.0 Hz,1H), 7.90 (s, 1H), 8.33 (d, J=6.0 Hz, 1H). [M+H] calc'd for C₁₄H₁₅N₃O₃,274; found, 274.

Example 81(R)-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

(R)-3-Methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid (80 mg, 0.29 mmol), HOBt (54 mg, 0.35 mmol) and EDC (84 mg, 0.44mmol) were combined in DMF (2 mL). Azetidine-3-carbonitrile HCl salt (52mg, 0.44 mmol) and N-methylmorpholine (130 μL, 1.17 mmol) were added,and the solution was stirred at room temperature for 2 h. Purificationby preparative HPLC (10-45% AcCN/water with 0.035% TFA) followed bypurification by silica gel chromatography (8% MeOH/DCM) gave the titlecompound as a white solid (28 mg, 28%). ¹H NMR (500 MHz, DMSO-d₆) δ 0.90(dd, J=6.5, 2.0 Hz, 3H), 1.06 (dd, J=6.5, 2.0 Hz, 3H), 2.42-2.51 (m,1H), 3.61-3.75 (m, 1H), 4.15-4.68 (m, 4H), 4.95-5.21 (m, 3H), 7.09 (t,J=5.0 Hz, 1H), 7.81 (d, J=12.5 Hz, 1H), 8.27 (t, J=5.0 Hz, 1H). [M+H]calc'd for C₁₈H₁₉N₅O₂, 338; found, 338.

PREPARATION W:(R)-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid

STEP A: (R)-benzyl 2-amino-3,3-dimethylbutanoate, TFA salt

Benzyl bromide (2.26 mL, 19.0 mmol) was added to a stirred solution of(R)-2-(tert-butoxycarbonylamino)-3-3-dimethylbutanoic acid (4.0 g, 17.3mmol) in AcCN (80 mL) at 0° C. DBU (3.13 mL, 20.8 mmol) was addedslowly, and the solution was stirred for 3 h while warming to roomtemperature. The solution was concentrated in vacuo, taken up in EtOAc,and washed with aqueous HCl (1N), aqueous NaHCO₃ (sat.), and brine. Theorganics were dried over MgSO₄) and concentrated. The resulting clearoil was dissolved in TFA/DCM (50%, 16 mL) and stirred for 1 h at roomtemperature. The solution was concentrated and purified by short silicacolumn (10% MeOH/DCM) to give the title compound as a white powder (5.02g, 87%). ¹H NMR (500 MHz, DMSO-d₆) δ 1.05 (s, 9H), 3.72 (s, 1H), 5.17(AB q, J=40.0, 12.0 Hz, 2H), 7.25-7.35 (m, 5H), 8.20 (br s, 2H).

STEP B: (R)-benzyl3,3-dimethyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate

Sodium triacetoxyborohydride (665 mg, 3.14 mmol) and (R)-benzyl2-amino-3,3-dimethylbutanoate, TFA salt (1.05 g, 2.85 mmol) werecombined in DCM (15 mL). The reaction mixture was stirred for 20 min atroom temperature and then cooled to 0° C.4-Formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (900 mg,2.61 mmol) was added, and the reaction mixture was stirred for 1 h. Thesolution was concentrated in vacuo to afford a tan foam, which wasre-dissolved in THF (40 mL). HATU (1.49 g, 3.92 mmol) andN-methylmorpholine (436 μL, 3.92 mmol) were added, and the reactionmixture was stirred at 52° C. for 2 h. Additional HATU (750 mg, 1.96mmol) and N-methylmorpholine (218 μL, 1.96 mmol) were added. Thereaction mixture was stirred for an additional 2 h, cooled, diluted withEtOAc, and washed with brine. The organics were dried over MgSO₄ andconcentrated in vacuo. Purification by silica gel chromatography (1:2:2EtOAc/Hexanes/DCM) gave the title compound as a pale yellow oil/foam(970 mg, 70%). ¹H NMR (500 MHz, CDCl₃) δ 1.12 (s, 9H), 2.33 (s, 3H),5.06 (AB q, J=66.5, 24.0 Hz, 2H), 5.11 (s, 2H), 5.48 (br s, 1H), 6.98(d, J=5.0 Hz, 1H), 7.14-7.28 (m, 7H), 8.03-8.11 (m, 3H), 8.42 (d, J=5.0Hz, 1H). [M+H] calc'd for C₂₉H₂₉N₃O₅S, 532; found, 532.

STEP C:(R)-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid

A mixture of (R)-benzyl3,3-dimethyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate(950 mg, 1.79 mmol), MeOH (4 mL), and aqueous NaOH (1N, 2 mL) wasstirred at room temperature for 40 min. The mixture was diluted with DCMand washed with brine. The organics were dried over MgSO₄ andconcentrated in vacuo. Purification by silica gel chromatography (5%MeOH/DCM) gave a yellow oil (500 mg), which was taken up in MeOH andstirred with 10% Pd/C under a balloon of H₂ for 1 h at room temperature.The reaction mixture was filtered through Celite and concentrated invacuo to give the title compound as an off-white solid (380 mg, 74%). ¹HNMR (500 MHz, DMSO-d₆) δ 1.13 (s, 9H), 4.12 (br s, 1H), 5.05-5.15 (m,2H), 7.08 (d, J=5.0 Hz, 1H), 7.84 (d, J=2.5 Hz, 1H), 8.25 (d, J=5.0 Hz,1H). [M+H] calc'd for C₁₅H_(r)N₃O₃, 288; found, 288.

Example 82(R)-1-(3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

(R)-3,3-Dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid (80 mg, 0.278 mmol), HOBt hydrate (51.2 mg, 0.334 mmol), and EDChydrochloride (80 mg, 0.418 mmol) were combined in DMF (2 mL).Azetidine-3-carbonitrile hydrochloride (49.5 mg, 0.418 mmol) and4-methylmorpholine (0.124 mL, 1.114 mmol) were added, and the reactionmixture was stirred at room temperature for 2 h. The product waspurified by preparative HPLC (10-50% AcCN/H₂O with 0.035% TFA),concentrated in vacuo, and purified by flash column chromatography (8%MeOH/DCM) to afford the title compound (38 mg, 39%). ¹H NMR (500 MHz,CD₃OD) δ 1.17 (s, 9H), 3.58-3.72 (m, 1H), 4.13-4.65 (m, 4H), 5.35-5.45(m, 3H), 7.28-7.38 (m, 1H), 7.95 (d, J=15.5 Hz, 1H), 8.33-8.40 (m, 1H).[M+H] calc'd for C₁₉H₂₁N₅O₂, 352; found, 352.

Example 83(R)—N-(cyanomethyl)-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide

(R)-3,3-Dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid (40.0 mg, 0.139 mmol), HOBt hydrate (25.6 mg, 0.167 mmol), and EDChydrochloride (40.0 mg, 0.209 mmol) were combined in DMF (2 mL).2-Aminoacetonitrile (11.71 mg, 0.209 mmol) and 4-methylmorpholine (0.062mL, 0.557 mmol) were added, and the reaction mixture was stirred at roomtemperature for 2 h. The product was purified by preparative HPLC(10-45% AcCN/H₂O with 0.035% TFA), concentrated in vacuo, andlyophilized to afford the title compound as a pale yellow solid (36 mg,59%). ¹H NMR (500 MHz, DMSO-d₆) δ 1.09 (s, 9H), 4.01-4.12 (m, 2H),5.13-5.22 (m, 2H), 5.33 (br s, 1H), 7.10 (d, J=4.5 Hz, 1H), 7.87 (s,1H), 8.26 (d, J=4.5 Hz, 1H), 8.86 (br s, 1H), 12.25 (br s, 1H). [M+H]calc'd for C₁₇H₁₉N₅O₂, 326; found, 326.

Example 84(S)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-2-carbonitrile

(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol), HATU (15 mg, 0.039 mmol),(S)-pyrrolidine-2-carbonitrile hydrochloride (4 mg, 0.032 mmol), andN-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL).The reaction mixture was stirred under nitrogen at 40° C. for 10 min andthen at room temperature for 30 min. The solution was concentrated andpurified by preparative HPLC (10-50% AcCN/H₂O with 0.035% TFA) to affordthe title compound as a yellow film (4 mg, 29%). ¹H NMR (500 MHz, CD₃OD)δ 0.94 (d, J=6.9 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 1.04-1.13 (m, 1H),2.12-2.17 (m, 2H), 2.25-2.29 (m, 2H), 2.60-2.63 (m, 1H), 3.72-3.75 (m,1H), 3.83-3.87 (m, 1H), 4.90 (d, J=13.7 Hz, 1H), 5.05 (d, J=12.7 Hz,1H), 5.50 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 8.25 (s, 1H). [M+H] calc'dfor C₁₉H₂₀ClN₅O₂, 386; found, 386.

Example 85(R)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-2-carbonitrile

(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol), HATU (15 mg, 0.039 mmol),(R)-pyrrolidine-2-carbonitrile hydrochloride (4 mg, 0.032 mmol), andN-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL).The reaction mixture was stirred under nitrogen at 40° C. for 10 min andthen at room temperature for 30 min. The solution was concentrated andpurified by preparative HPLC (10-50% AcCN/H₂O with 0.035% TFA) to affordthe title compound as a white solid (2 mg, 18%). ¹H NMR (500 MHz, CD₃OD)δ 0.94 (d, J=6.9 Hz, 3H), 1.06 (d, J=6.3 Hz, 3H), 1.03-1.12 (m, 1H),2.12-2.17 (m, 2H), 2.25-2.27 (m, 2H), 2.59-2.63 (m, 1H), 3.72-3.74 (m,1H), 3.83-3.86 (m, 1H), 4.92 (d, J=5.9 Hz, 1H), 5.06 (d, J=13.2 Hz, 1H),5.46 (d, J=11.8 Hz, 1H), 7.86 (s, 1H), 8.25 (s, 1H). [M+H] calc'd forC₁₉H₂₀ClN₅O₂, 386; found, 386.

Example 86(2S,4S)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)-4-fluoropyrrolidine-2-carbonitrile

(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid (10 mg, 0.032 mmol)), HATU (15 mg, 0.039 mmol),(2S,4S)-4-fluoropyrrolidine-2-carbonitrile (4 mg, 0.032 mmol), andN-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL).The reaction mixture was stirred under nitrogen at 40° C. for 10 min andthen at room temperature for 30 min. The solution was concentrated andpurified by preparative HPLC (10-50% AcCN/H₂O with 0.035% TFA) to affordthe title compound as a white solid (2 mg, 12%). ¹H NMR (500 MHz, CD₃OD)δ 0.94 (d, J=6.3 Hz, 3H), 1.05 (d, J=6.3 Hz, 3H), 1.03-1.15 (m, 1H),2.56-2.65 (m, 3H), 23.89-3.91 (m, 1H), 4.25-4.30 (m, 1H), 4.83-4.87 (m,1H), 5.09-5.13 (m, 1H), 5.39-5.41 (m, 1H), 5.47-5.66 (m, 1H), 7.87 (s,1H), 8.27 (s, 1H). [M+H] calc'd for C₁₉H₁₉ClFN₅O₂, 404; found, 404.

PREPARATION X:(R)-3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid

STEP A:(R)-3,3-dimethyl-2-(6-methyl-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid

(R)-Benzyl2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate(10 mg, 0.018 mmol), Pd(Ph₃P)₄ (10 mg, 0.009 mmol), and dioxane (1 mL)were combined in a 2 mL microwave vial. The mixture was purged withnitrogen, and trimethylaluminum (2.0M/toluene, 0.053 mL, 0.11 mmol) wasadded. The vial was sealed and the reaction mixture was heated in aBiotage Initiator™ microwave for 1 h at 120° C. The reaction wasrepeated three times with an increased amount of (R)-benzyl2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate(30 mg) in each reaction. The reaction mixtures were combined and theresulting mixture was concentrated and purified by preparative HPLC(30-70% AcCN/H₂O with 0.035% TFA) to afford the title compound as ayellow oil (36 mg, 44%). ¹H NMR (500 MHz, CD₃OD) δ 1.21 (s, 9H), 2.30(s, 3H), 2.36 (s, 3H), 4.94 (s, 1H), 5.07 (d, J=18.6 Hz, 1H), 5.21 (d,J=19.0 Hz, 1H), 7.36 (d, J=8.3 Hz, 2H), 8.04 (d, J=4.9 Hz, 2H), 8.10 (s,1H), 8.22 (s, 1H). [M+H] calc'd for C₂₃H₂₅N₃O₅S, 456; found, 456

STEP B:(R)-3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid

(R)-3,3-Dimethyl-2-(6-methyl-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid (36 mg, 0.079 mmol)) was dissolved in THF (3 mL), MeOH (3 mL) andaqueous NaOH (1N, 3 mL) in a 50 mL round bottom flask. The reactionmixture was heated at 50° C. for 30 min in an oil bath then cooled toroom temperature. The solution was concentrated and purified bypreparative HPLC (10-35% AcCN/H₂O with 0.035% TFA) to give the titlecompound (10 mg, 42%). ¹H NMR (500 MHz, CD₃OD) δ 1.25 (s, 9H), 2.29 (s,3H), 4.87 (s, 1H), 5.21 (d, J=19.5 Hz, 1H), 5.37 (d, J=19.5 Hz, 1H),7.87 (s, 1H), 8.23 (s, 1H). [M+H] calc'd for C₁₆H₁₉N₃O₃, 302; found,302.

Example 87(R)-1-(3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

(R)-3,3-Dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoicacid (10 mg, 0.033 mmol), DMAP (6 mg, 0.05 mmol), 4-methylmorpholine(0.015 mL, 0.13 mmol), EDC hydrochloride (10 mg, 0.050 mmol), HOBthydrate (8 mg, 0.050 mmol) and azetidine-3-carbonitrile hydrochloride (6mg, 0.050 mmol) were dissolved in DMF (2 mL). The reaction mixture wasstirred under nitrogen at room temperature for 3 h. The solution wasconcentrated and purified by preparative HPLC (10-30% AcCN/H₂O with0.035% TFA) to give the title compound (1.4 mg, 12%). ¹H NMR (500 MHz,CD₃OD) δ 1.18 (s, 9H), 2.35 (d, J=8.8 Hz, 3H) 4.17-4.18 (m, 1H),4.29-4.31 (m, 2H), 4.52-4.62 (m, 1H), 4.64-4.69 (m, 1H), 5.19-5.23 (m,2H), 5.45 (s, 1H), 7.83 (d, J=16.1 Hz, 3H), 8.19 (s, 1H). [M+H] calc'dfor C₂₀H₂₃N₅O₂, 366; found, 366

Example 88(R)-1-(3-methyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile(30 mg, 0.081 mmol), Pd(Ph₃P)₄ (47 mg, 0.04 mmol), and dioxane (2 mL)were combined in a 5 mL microwave vial. The mixture was purged withnitrogen, and trimethylaluminum (2.0M/toluene, 0.24 mL, 0.48 mmol) wasadded. The vial was sealed and the reaction mixture was heated in aBiotage Initiator™ microwave for 1 h at 120° C. The reaction wasrepeated 4 times at the same scale. The reaction mixtures were combined,and the resulting mixture was quenched with water (0.5 mL),concentrated, and purified by preparative HPLC (10-30% AcCN/H₂O with0.035% TFA) followed by flash chromatography (5% MeOH/95% DCM) to givethe title compound as a light yellow solid (41 mg, 29%). ¹H NMR (500MHz, CD₃OD) δ 0.92 (d, J=6.8 Hz, 3H), 1.07 (dd, J=15.9, 6.1 Hz, 3H),2.42 (d, J=6.35 Hz, 3H), 3.69-3.77 (m, 1H), 4.19-4.22 (m, 1H), 4.32-4.34(m, 1H), 4.53-4.59 (m, 1H), 4.68-4.72 (m, 1H), 5.20-5.33 (m, 3H), 7.98(d, J=19.5 Hz, 1H), 8.27 (s, 1H). [M+H] calc'd for C₁₉H₂₁N₅O₂, 352;found, 352.

Table 2, below, lists JAK3 and JAK2 inhibition data for many of thecompounds described in the examples. The compounds were tested inaccordance with the assay described on page 27 of the specification. Theinhibition data is reported as pIC₅₀, i.e., −log₁₀(IC₅₀), where IC₅₀ isthe molar concentration at 50% inhibition. Larger pIC₅₀ values representhigher potency.

TABLE 2 JAK2 and JAK3 Inhibition JAK3 JAK2 Example No. pIC₅₀ pIC50 2 5.45.2 3 5.8 6.1 6 6.3 7.1 9 8.0 7.7 10 7.0 7.1 11 6.5 6.4 12 5.1 5.5 135.5 5.3 16 7.3 8.0 17 7.9 8.3 18 4.7 4.7 19 6.5 5.4 20 7.1 5.8 21 6.96.1 22 7.5 6.2 23 6.4 5.4 24 5.8 4.9 25 6.7 5.8 26 8.0 6.9 27 6.6 5.5 286.4 5.0 29 6.8 5.5 30 5.9 5.5 31 4.7 4.7 32 8.0 6.7 33 7.4 6.1 34 7.86.6 35 6.5 5.6 36 6.9 6.0 37 7.2 5.8 38 7.5 6.0 39 8.7 7.5 40 7.3 5.9 418.4 7.3 42 8.2 6.9 43 6.1 4.9 44 6.9 5.8 45 7.2 5.7 46 6.6 5.8 47 6.95.6 48 6.6 5.3 49 7.0 5.7 50 7.1 5.8 51 8.3 6.8 52 8.0 6.7 53 7.9 6.6 545.7 4.5 55 6.0 4.9 56 6.2 5.0 57 7.1 5.8 58 6.5 5.5 59 5.2 4.7 60 6.15.0 61 5.2 4.7 62 5.8 4.9 63 6.2 5.2 64 5.6 4.7 65 5.7 5.2 66 5.4 4.7 676.6 5.3 68 5.6 4.7 69 6.2 5.0 70 6.3 5.0 71 6.1 5.3 72 6.9 5.7 73 6.85.5 74 6.1 5.1 75 7.5 6.1 76 7.2 6.0 77 7.2 5.8 78 5.4 5.0 79 6.9 5.6 807.8 6.4 81 8.3 6.9 82 8.7 7.4 83 7.9 6.6 84 6.7 5.5 85 7.0 5.8 86 7.66.4 87 8.5 7.3 88 8.8 7.6

1. A method of treating a disease, disorder or condition associated withJAK in a subject, the method comprising administering to the subject aneffective amount of a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: G₁ is selectedfrom the group consisting of N and CR₈; R₁ is selected from the groupconsisting of optionally substituted C₃₋₈ cycloalkyl, optionallysubstituted C₃₋₆ heterocycloalkyl, optionally substituted C₄₋₁₄ aryl,optionally substituted C₁₋₁₀ heteroaryl, and optionally substituted C₁₋₆alkyl; R₂ and R₃ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁₋₄ alkyl, or R₂, R₃,and the carbon atom to which they are attached form a carbonyl; R₄ isselected from the group consisting of hydrogen, optionally substitutedC₁₋₄ alkyl, optionally substituted C₁₋₄ alkoxy, halo, hydroxy, andamino; R₅ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₄ alkyl, C₃₋₈ cycloalkyl, and halo; R₆ and R₇ are eachindependently selected from the group consisting of hydrogen andoptionally substituted C₁₋₄ alkyl, or R₆, R₇, and the carbon atom towhich they are attached form a carbonyl; R₈ is selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₅ oxycarbonyl, cyano, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₄₋₁₄ aryl,optionally substituted C₁₋₁₀ heteroaryl, and halo; and with the provisothat no more than one carbonyl is formed from R₂ and R₃ and R₆ and R₇.2. A method according to claim 1, wherein each of R₄ and R₅ arehydrogen.
 3. A method according to claim 1, wherein G is CR₈.
 4. Amethod according to claim 3, wherein G is CR₈ and R₈ is selected fromhydrogen, halo, and optionally substituted C₁₋₆ alkyl.
 5. A methodaccording to claim 4, wherein G is CR₈ and R₈ is selected from hydrogen,halo, and C₁₋₄ alkyl.
 6. A method according to claim 1, wherein G is N.7. A method according to claim 1, wherein R₁ is optionally substitutedC₃₋₈ cycloalkyl.
 8. A method according to claim 1, wherein R₁ isoptionally substituted C₃₋₆ heterocycloalkyl.
 9. A method according toclaim 1, wherein R₁ is optionally substituted C₄₋₁₄ aryl.
 10. A methodaccording to claim 1, wherein R₁ is optionally substituted C₁₋₁₀heteroaryl.
 11. A method according to claim 1, wherein R₁ is optionallysubstituted C₁₋₆ alkyl.
 12. A method according to claim 1, wherein R₂,R₃, and the carbon atom to which they are attached form a carbonyl. 13.A method according to claim 12, wherein each of R₆ and R₇ is hydrogen.14. A method according to claim 1, wherein R₆, R₇, and the carbon atomto which they are attached form a carbonyl.
 15. A method according toclaim 14, wherein each of R₂ and R₃ is hydrogen.
 16. A method accordingto claim 1, in which the compound is selected from: tert-butyl4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate;4-(piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;3-oxo-3-(4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)propanenitrile;tert-butyl4-methyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate;4-(4-methylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;3-(4-methyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)-3-oxopropanenitrile;tert-butyl4-ethyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate;4-(4-ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;3-(4-ethyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)-3-oxopropanenitrile;4-(pentan-3-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;4-(1-cyclopropyl-3-hydroxypropyl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;tert-butyl3-((5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)methyl)pyrrolidine-1-carboxylate;4-(pyrrolidin-3-ylmethyl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridine-5(1H)-one;tert-butyl3-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate;4-(piperidin-3-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;4-(4-ethyl-1-propionylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;4-(4-ethyl-1-(pyrimidin-4-yl)piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;(S)-4-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-4-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-4-(3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-4-(4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(2R,3R)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)pentanamide;(2R,3S)—N-cyclopentyl-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)pentanamide;(R)—N-cyclopentyl-2-cyclopropyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)acetamide;(R)—N-cyclopentyl-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)—N,2-dicyclopentyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)acetamide;(R)—N-cyclopentyl-4,4,4-trifluoro-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)—N-cyclopentyl-3-hydroxy-3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamide;N-cyclopentyl-1-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)cyclopentanecarboxamide;(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(cyanomethyl)-3-methylbutanamide;1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-3-carbonitrile;(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)piperidine-4-carbonitrile;(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(4-cyanophenyl)-3-methylbutanamide;(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(3-cyanophenyl)-3-methylbutanamide;(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N—((S)-1-cyanobutan-2-yl)-3-methylbutanamide;(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N—((R)-1-cyanobutan-2-yl)-3-methylbutanamide;(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile;(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(2-cyanoethyl)-3,3-dimethylbutanamide;(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoyl)azetidine-3-carbonitrile;(R)-1-(2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile;(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoicacid;R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(tetrahydrofuran-3-yl)butanamide;(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(1,1-dioxidotetrahydrothien-3-yl)butanamide;(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(2-(methylsulfonyl)ethyl)butanamide;(R)—N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide;4-{(1R)-1-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-2-methylpropyl}-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)—N-(cyclopropylmethoxy)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide;(2R)—N-(3,3-difluorocyclopentyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide;(R)-3-(fluoromethyl)-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;(R)-1-(2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)-3-methylazetidine-3-carbonitrile;(R)-3-methyl-1(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;(R)-4-(1-morpholino-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-4-(1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;4-((2R)-1-(3-hydroxypyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)—N-cyclopentyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;4-((2R)-1-(3-(4-fluorophenyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;4-((2R)-1-(3-(dimethylamino)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;4-((2R)-1-(3-(methoxymethyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;4-((2R)-1-(3-methylpiperidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-4-(1-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-4-(1-(4-(methylsulfonyl)piperazin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-4-(1-oxo-1-(4-(pyridin-2-yl)piperazin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)—N-cyclopropyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)—N-(cyclopropylmethyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)—N-isobutyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)—N-isobutyl-N-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;—N-(1-hydroxypropan-2-yl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)—N-(2-hydroxy-2-methylpropyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)—N—((S)-2,3-dihydroxypropyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(R)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-phenylbutanamide;(R)—N-(1-(methylsulfonyl)piperidin-4-yl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(2R)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-((tetrahydrofuran-2-yl)methyl)butanamide;(2R)—N-(1-cyanoethyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide;(R)-4-(1-(3,3-difluoroazetidin-1-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-4-(1-(1,1-dioxidothiazolidin-3-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N,3-dimethyl-N-(2-(methylsulfonyl)ethyl)butanamide;(R)—N-(cyanomethyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N,3-dimethylbutanamide;(R)-4-(1-(3-(difluoromethyl)azetidin-1-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;(R)-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;(R)-1-(3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;(R)—N-(cyanomethyl)-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;(S)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-2-carbonitrile;(R)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-2-carbonitrile;(2S,4S)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)-4-fluoropyrrolidine-2-carbonitrile;(R)-1-(3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;(R)-1-(3-methyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;stereoisomers of any of the aforementioned compounds; andpharmaceutically acceptable salts of any one of the aforementionedstereoisomers or compounds. 17-20. (canceled)
 21. A method according toclaim 1, wherein the disease, disorder or condition is selected fromallergic rhinitis, allergic asthma, atopic dermatitis, rheumatoidarthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis,immune thrombocytopenic purpura, chronic obstructive pulmonary disease,and thrombosis.
 22. A method according to claim 1, further comprisingadministering an effective amount of at least one additionalpharmacologically active agent.
 23. A method according to claim 22,wherein the additional pharmacologically active agent is a DMARD.
 24. Amethod according to claim 23, wherein the DMARD is methotrexate.
 25. Amethod of treating a disease, disorder or condition associated with JAKin a subject, the method comprising administering to the subject apharmaceutical composition, the pharmaceutical composition comprising acompound or pharmaceutically acceptable salt as defined in claim 1, anda pharmaceutically acceptable excipient.
 26. A method according to claim25, wherein the disease, disorder or condition is selected from allergicrhinitis, allergic asthma, atopic dermatitis, rheumatoid arthritis,multiple sclerosis, systemic lupus erythematosus, psoriasis, immunethrombocytopenic purpura, chronic obstructive pulmonary disease, andthrombosis.